Reactivity of asymmetric benzo-condensed diazines with nitrilimine dipoles in the 1,3-dipolar cycloaddition reactions

The reactivity of asymmetric benzo-condensed diazines in the 1,3-dipolar cycloaddition reactions with nitrilimines was investigated. The results demonstrated that, at variance with the symmetric quinoxaline, a certain grade of diastereoselectivity emerged. Moreover in the case of the 5-methylquinoxaline and quinazoline a mono-cycloadduct was obtained.     

Reconciling Electrostatic and n→π* Orbital Contributions in Carbonyl Interactions

Interactions between carbonyl groups are prevalent in protein structures. Earlier investigations identified dominant electrostatic dipolar interactions, while others implicated lone pair n→π* orbital delocalisation. Here these observations are reconciled. A combined experimental and computational approach confirmed the dominance of electrostatic interactions in a new series of synthetic molecular balances, while also highlighting the distance‐dependent observation of inductive polarisation manifested by n→π* orbital delocalisation. Computational fiSAPT energy decomposition and natural bonding orbital analyses correlated with experimental data to reveal the contexts in which short‐range inductive polarisation augment electrostatic dipolar interactions. Thus, we provide a framework for reconciling the context dependency of the dominance of electrostatic interactions and the occurrence of n→π* orbital delocalisation in C=O???C=O interactions.     

Magnitude and origin of the attraction and directionality of the halogen bonds of the complexes of C6F5X and C6H5X (X = I, Br, Cl and F) with pyridine

The geometries and interaction energies of complexes of pyridine with C₆F₅X, C₆H₅X (X=I, Br, Cl, F and H) and R_FI (R_F=CF₃, C₂F₅ and C₃F₇) have been studied by ab initio molecular orbital calculations. The CCSD(T) interaction energies (E_int) for the C₆F₅X–pyridine (X=I, Br, Cl, F and H) complexes at the basis set limit were estimated to be ?5.59, ?4.06, ?2.78, ?0.19 and ?4.37 kcal mol^?1, respectively, whereas the E_int values for the C₆H₅X–pyridine (X=I, Br, Cl and H) complexes were estimated to be ?3.27, ?2.17, ?1.23 and ?1.78 kcal mol^?1, respectively. Electrostatic interactions are the cause of the halogen dependence of the interaction energies and the enhancement of the attraction by the fluorine atoms in C₆F₅X. The values of E_int estimated for the R_FI–pyridine (R_F=CF₃, C₂F₅ and C₃F₇) complexes (?5.14, ?5.38 and ?5.44 kcal mol^?1, respectively) are close to that for the C₆F₅I–pyridine complex. Electrostatic interactions are the major source of the attraction in the strong halogen bond although induction and dispersion interactions also contribute to the attraction. Short‐range (charge‐transfer) interactions do not contribute significantly to the attraction. The magnitude of the directionality of the halogen bond correlates with the magnitude of the attraction. Electrostatic interactions are mainly responsible for the directionality of the halogen bond. The directionality of halogen bonds involving iodine and bromine is high, whereas that of chlorine is low and that of fluorine is negligible. The directionality of the halogen bonds in the C₆F₅I– and C₂F₅I–pyridine complexes is higher than that in the hydrogen bonds in the water dimer and water–formaldehyde complex. The calculations suggest that the C? I and C? Br halogen bonds play an important role in controlling the structures of molecular assemblies, that the C? Cl bonds play a less important role and that C? F bonds have a negligible impact.     

Insights into Intramolecular Trp and His Side‐Chain Orientation and Stereospecific π Interactions Surrounding Metal Centers: An Investigation Using Protein Metal‐Site Mimicry in Solution

Metal‐binding scaffolds incorporating a Trp/His‐paired epitope are instrumental in giving novel insights into the physicochemical basis of functional and mechanistic versatility conferred by the Trp–His interplay at a metal site. Herein, by coupling biometal site mimicry and ¹H and ¹³C NMR spectroscopy experiments, modular constructs EDTA‐(L ‐Trp, L ‐His) (EWH; EDTA=ethylenediamino tetraacetic acid) and DTPA‐(L ‐Trp, L ‐His) (DWH; DTPA=diethylenetriamino pentaacetic acid) were employed to dissect the static and transient physicochemical properties of hydrophobic/hydrophilic aromatic interactive modes surrounding biometal centers. The binding feature and identities of the stoichiometric metal‐bound complexes in solution were investigated by using ¹H and ¹³C NMR spectroscopy, which facilitated a cross‐validation of the carboxylate, amide oxygen, and tertiary amino groups as the primary ligands and indole as the secondary ligand, with the imidazole (Im) N3 nitrogen being weakly bound to metals such as Ca²⁺ owing to a multivalency effect. Surrounding the metal centers, the stereospecific orientation of aromatic rings in the diastereoisomerism is interpreted with the Ca²⁺–EWH complex. With respect to perturbed Trp side‐chain rotamer heterogeneity, drastically restricted Trp side‐chain flexibility and thus a dynamically constrained rotamer interconversion due to π interactions is evident from the site‐selective ¹³C NMR spectroscopic signal broadening of the Trp indolyl C3 atom. Furthermore, effects of Trp side‐chain fluctuation on indole/Im orientation were the subject of a 2D NMR spectroscopy study by using the Ca²⁺‐bound state; a C? H2(indolyl)/C? H5(Im⁺) connectivity observed in the NOESY spectra captured direct evidence that the N? H1 of the Ca²⁺–Im⁺ unit interacted with the pyrrole ring of the indole unit in Ca²⁺‐bound EWH but not in DWH, which is assignable to a moderately static, anomalous, T‐shaped, interplanar π⁺–π stacking alignment. Nevertheless, a comparative ¹³C NMR spectroscopy study of the two homologous scaffolds revealed that the overall response of the indole unit arises predominantly from global attractions between the indole ring and the entire positively charged first coordination sphere. The study thus demonstrates the coordination‐sphere/geometry dependence of the Trp/His side‐chain interplay, and established that π interactions allow ¹³C NMR spectroscopy to offer a new window for investigating Trp rotamer heterogeneity near metal‐binding centers.     

On the 1,3-dipolar cycloaddition reactions of indenone with N-N-C dipoles: density functional theory calculations

Density functional theory (DFT) calculations at the B3LYP/6-311G* theoretical level have been performed to study the 1,3-dipolar cycloaddition (1,3-DC) reactions between indenone (1) and different 1,3-dipoles (diazomethane and N-methyl C-methoxy carbonyl nitrilimine, compounds 2 and 3, respectively). The geometrical and energetic properties were analysed for the different reactives, transition states and cycloadducts formed (compounds 4-11). The reactions proceed in the gas-phase by an asynchronous concerted mechanism, yielding different regiochemistry dependent on the 1,3-dipole chosen, although with dipole 3 some degree of synchrony was found in the formation of cycloadduct 5. The 1,3-DC between 1 and 3 was regioselective, being the cycloadduct 11 favoured against 9. The NMR chemical shift parameters (GIAO method) were also calculated for the reactives and cycloadducts.     

Synthesis of Naphthyridine Dimers with Conformational Restriction and Binding to DNA and RNA

One of the important determinants in the efficiency of a molecular interaction is the necessity for conformational changes in host and/or guest molecules upon binding. In small‐molecule interactions with nucleic acids, conformational changes on both molecules are often involved, especially in intercalating binding. Mismatch binding ligands (MBLs) we described here consist of two heterocycles that predominantly exist in one conformation, so it is of interest to determine if such molecules can bind to any DNA and RNA structures. One molecule, 1 ‐NHR, which predominantly exists as the unstacked conformation in aqueous solvent, has been successfully synthesized and characterized. Compound 1 ‐NHR did not efficiently bind to GX/Y DNA and RNA sequences, but the binding pattern is different from that of authentic MBL naphthyridine carbamate dimer. In vitro selection of RNA that specifically binds to 1 ‐NHR was performed from pre‐miR‐29a loop library RNA, and one RNA, to which 1 ‐NHR bound with high affinity, has been successfully identified. Although it was anticipated that 1 ‐NHR, with a predominantly unstacked conformation, would show entropy‐driven binding, isothermal titration calorimetry analysis suggested that the binding of 1 ‐NHR to RNA was enthalpy driven with an apparent K _d of about 100 nm .     

Diastereomer-differentiating hydrolysis of 1,3-diol-acetonides: a simplified procedure for the separation of syn- and anti-1,3-diols

[reaction: see text] A new method to facilitate the separation of diastereomeric syn- and anti-1,3-diols is described. The method relies on the different hydrolysis rates of the corresponding diastereomeric acetonides. Treatment of a dichloromethane solution of syn- and anti-1,3-diol-acetonide with a catalytic amount of diluted aqueous hydrochloric acid leads to the selective cleavage of the anti diastereomer. The resulting anti-1,3-diol can be easily separated from the unchanged syn-1,3-diol-acetonide.     

Probing the structural and electronic effects to stabilize nonplanar forms of thioamide derivatives: A computational study

Density functional calculations have been performed to examine the stability of nonplanar conformations of thioamide derivatives. Electrostatic, orbital, and ring strain effects were invoked to stabilize the nonplanar conformations of thioamide systems 2 – 7 . Electrostatic interactions helped to achieve the twisted forms of thioamide derivatives; however, pyramidal forms predicted to be the global minimum. Negative hyperconjugative type interactions enhanced the stability of the twisted form 4b when compared with the planar form 4a . The influence of ring strain effect to achieve the twisted form of thioamide was observed with azirine ring. The predictions made with B3LYP/cc‐pVDZ+ level of theory was found to be in good agreement with more accurate CBS‐QB3 method. The solvent calculations performed with polarized continuum solvation model suggest that the relative stabilities of the nonplanar forms of thioamide derivatives are in general similar to the gas phase results. The importance of hydrogen bonding interactions between the solvent molecules and thioamide derivatives was observed toward the enhanced stability of twisted forms using a combination of explicit solvent molecules and continuum model. The natural bond orbital analysis confirmed the participation of n_N → π*_C?S delocalizations in the planar forms and corroborated the earlier reports on larger delocalizations in thioamide systems. Furthermore, the influence of electrostatic and ring strain effects on the amide, natural amides, and selenoamide has also been studied. © 2011 Wiley Periodicals, Inc. J Comput Chem 2011     

Ab initio studies of the characteristics of hydrogen bonds involving aromatically bound hydroxyl and amino groups and the effects of aromatic fluorine substitution on these interactions

In this work, we study the hydrogen bonds (H‐bonds) involving hydroxyl and amino groups bonded to phenyl and pyrimidine rings (as H‐bond donors). These types of interactions play important roles in the recognition of ligands by proteins and are also important in the design of materials. The effects of aromatic fluorine substitutions on aromatic rings are also investigated, and it is found that these substitutions can have large effects on the hydrogen bonding interactions that occur in our model systems, making them substantially stronger. This finding offers a new mechanism for the modification of these types of interactions, potentially opening new paths in the design of novel pharmaceuticals and materials. © 2009 Wiley Periodicals, Inc. Int J Quantum Chem, 2010     

First hyperpolarizabilities of 1,3,5-tricyanobenzene derivatives: origin of larger beta values for the octupoles than for the dipoles.

A series of donor-acceptor substituted stilbene and diphenylacetylene derivatives and their octupolar analogues have been synthesized and the linear and nonlinear optical properties (beta) studied by both experiments and theoretical calculation. The lambda(max) of the dipoles increases with the conjugation length and is always larger when the C=C bond is used, instead of the C[triple bond]C bond, as the conjugation bridge. Although the lambda(max) values of the octupoles show no clear trend, they are much larger than those of the dipoles. The beta(0) values of the dipoles increase with conjugation length and as the conjugation bridge is changed from the C[triple bond]C to C=C bond. This increase is accompanied by an increase in either lambda(max) or the oscillator strength. Similarly, the beta(0) values of the octupoles increase with the conjugation length and with a change in the donor in the order: NEt2 < N(i-amyl)Ph < NPh2. Moreover, beta(yyy)/beta(zzz) ratios are in the range of 1.6-3.9 and decrease with the conjugation length. Beta values calculated by the finite-field and sum-over-states methods are in good agreement with the experimental data. Also, there is a parallel relationship between the calculated beta values and bond length alternation (BLA). From these results, the origin of the larger beta values for octupoles than for dipoles is assessed.     

Iron twin-coronet porphyrins as models of myoglobin and hemoglobin: amphibious electrostatic effects of overhanging hydroxyl groups for successful CO/O2 discrimination

Inspired by the observation of polar interactions between CO and O(2) ligands and the peptide residues at the active site of hemoglobin and myoglobin, we synthesized two kinds of superstructured porphyrins: TCP-IM, which contains a linked imidazole ligand, and TCP-PY, which contains a linked pyridine ligand, and examined the thermodynamic, kinetic, and spectroscopic (UV/Vis, IR, NMR, and resonance Raman) properties of their CO and O(2) complexes. On both sides of each porphyrin plane, bulky binaphthyl bridges form hydrophobic cavities that are suitable for the binding of small molecules. In the proximal site, an imidazole or pyridine residue is covalently fixed and coordinates axially to the central iron atom. In the distal site, two naphtholic hydroxyl groups overhang toward the center above the heme. The CO affinities of TCPs are significantly lower than those of other heme models. In contrast, TCPs have moderate O(2) binding ability. Compared with reported model hemes, the binding selectivity of O(2) over CO in TCP-IM and TCP-PY complexes is greatly improved. The high O(2) selectivity of the TCPs is mainly attributable to a low CO affinity. The comparison of k(on)(CO) values of TCPs with those of unhindered hemes indicates the absence of steric hindrance to the intrinsically linear CO coordination to Fe(II) in TCP-IM and TCP-PY. The abnormally large k(off)(CO) values are responsible for the low CO affinities. In contrast, k(off)(O(2)) of TCP-PY is smaller than those of other pyridine-coordinated model hemes. For the CO adducts of TCPs, unusually low nu(Fe-CO) and unusually high nu(C-O) frequencies are observed. These results can be ascribed to decreased back-bonding from the iron atom to the bound CO. The lone pairs of the oxygen atoms of the hydroxyl groups prevent back-bonding by exertion of a strong negative electrostatic interaction. On the other hand, high nu(Fe-O(2)) frequencies are observed for the O(2) adducts of TCPs. In the resonance Raman (RR) spectrum of oxy-TCP-IM, we observed simultaneous enhancement of the Fe-O(2) and O-O stretching modes. Furthermore, direct evidence for hydrogen bonding between the hydroxyl groups and bound dioxygen was obtained by RR and IR spectroscopy. These spectroscopic data strongly suggest that O(2) and CO binding to TCPs is controlled mainly by the two different electrostatic effects exerted by the overhanging OH groups: destabilization of CO binding by decreasing back-bonding and stabilization of O(2) binding by hydrogen bonding.     

Conformational transition of polyelectrolytes in mixed solvent by dielectric spectroscopy: Electrostatic and hydrophobic interactions

We studied conformational transition of poly(acrylic acid)‐graft‐dodecyl (PAA‐g‐dodecyl), and PAA‐graft‐poly(ethylene oxide)‐graft‐dodecyl (PAA‐g‐PEO‐g‐dodecyl) molecules in DMF/H₂O solvent by dielectric analysis method utilizing a double‐layer polarization theory. In addition to the hydrophobic interaction which has been demonstrated to be vital for their conformational transition with water content, it is confirmed that the electrostatic interaction is crucial. For PAA‐g‐dodecyl molecules, at a critical value of water content, a peak value of correlation length is reached originating from the delicate balance between electrostatic and hydrophobic interactions. For PAA‐g‐PEO‐g‐dodecyl molecules, chains conformation is mainly determined by electrostatic interaction over the entire range of water content due to the low content of dodecyl groups. Meanwhile, H‐bond associative interaction prevents the dissociation of free carboxyl groups over the range of lower water content, thus their stretched transition moves to higher water content. Our results provide the underlying insights needed to understand solvent effect on the conformational transition for polyelectrolytes with hydrophobic groups. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2019 , 57, 1716–1724     

Study on 1,3,5‐Triazine Chemistry in Dehydrocondensation: Gauche Effect on the Generation of Active Triazinylammonium Species

The reaction of 2‐chloro‐4,6‐dimethoxy‐1,3,5‐triazine (CDMT) with various nitrogen‐containing compounds, particularly tertiary amines (tert‐amines), has been studied for the preparation of 2‐(4,6‐dimethoxy‐1,3,5‐triazinyl)trialkylammonium salts [DMT‐Am(s)]. DMT‐Ams derived from aliphatic tert‐amines exhibited activity for the dehydrocondensation between a carboxylic acid and an amine to form an amide in a model reaction. Based on a conformational analysis of DMT‐Ams and tert‐amines by NMR and X‐ray diffraction methods, we concluded that a β‐alkyl group maintained in a gauche relationship with the nitrogen lone pair of tert‐amines significantly hinders the approach of CDMT to the nitrogen. Thus, trimethylamine and quinuclidine without such alkyl groups readily react with CDMT whereas triethylamine, possessing two or three such gauche β‐alkyl groups in the stable conformations, does not react at all. The theory of “gauche β‐alkyl group effect” proposed here provides useful guidelines for the preparation of DMT‐Ams possessing various tertiary amine moieties. An investigation of the dehydrocondensation activity of tert‐amines in a CDMT/tert‐amine system that involves in situ generation of DMT‐Am, showed that the gauche effect of the β‐alkyl group becomes quite pronounced; the yield of the amide decreases significantly with tert‐amines possessing an unavoidable gauche β‐alkyl group. Thus, the tert‐amine/CDMT systems are useful for judging whether tert‐amines can readily react with CDMT without isolation of DMT‐Ams.     

Exploring the potential energy surfaces of association of NO with aminoacids and related organic functional groups: the role of entropy of association

Association between NO and each of the 20 amino acids and their related organic functional groups was studied by exploring the configuration space of the potential energy of association surface by using the multiple minima hypersurface procedure. AM1 semiempirical Hamiltonian was used in order to explore such complex hypersurfaces of biological molecular interactions at finite computational times. An appropriate test with a set of NO and small molecule complexes obtained at the MP2/6-311++g(2d,2p) level of theory was also carried out. Stabilization energies of larger models were also evaluated at the conventional PBE1PBE/6-31g(d,p) DFT level. NO–aminoacid hypersurface explorations yielded that interactions of NO with NH group together with the C=O belonging to the backbone appeared predominant in all cases. Models of polar aminoacids and NO also show stable interactions with the lateral chains. Interactions with charged amino acids were found as the most stable and Lys was, undoubtedly, the preferred association. The study of these kinds of interactions must take into account the deepest and other minima because the entropy of association plays an important role. Contribution to the Serafin Fraja Memorial Issue. Dedicated to Prof. Serafín Fraga, an unforgettable friend.     

Selectivity in the addition reactions of organometallic reagents to aziridine-2-carboxaldehydes: the effects of protecting groups and substitution patterns

Good to excellent stereoselectivity has been found in the addition reactions of Grignard and organozinc reagents to N-protected aziridine-2-carboxaldehydes. Specifically, high syn selectivity was obtained with benzyl-protected cis, tert-butyloxycarbonyl-protected trans, and tosyl-protected 2,3-disubstituted aziridine-2-carboxaldehydes. Furthermore, rate and selectivity effects of ring substituents, temperature, solvent, and Lewis acid and base modifiers were studied. The diastereomeric preference of addition is dominated by the substrate aziridines' substitution pattern and especially the electronic character and conformational preferences of the nitrogen protecting groups. To help rationalize the observed stereochemical outcomes, conformational and electronic structural analyses of a series of model systems representing the various substitution patterns have been explored by density functional calculations at the B3LYP/6-31G* level of theory with the SM8 solvation model to account for solvent effects.     

Effect of Soft Preheating of Bovine Serum Albumin on the Complexation with Oligochitosan: Structure and Conformation of BSA in the Complex

Phase analysis, spectroscopic, and light scattering methods are applied to investigate the peculiarities of the interaction of oligochitosan (OCHI) with native and preheated bovine serum albumin (BSA) as well as the conformational and structural changes of BSA in BSA/OCHI complex. As shown, untreated BSA binds with OCHI mainly forming soluble electrostatic nanocomplexes, with the binding causing an increase in BSA helicity without a change in the local tertiary structure and thermal stability of BSA. In contrast, soft preheating at 56 °C enhances the complexation of BSA with OCHI and slightly destabilizes the secondary and local tertiary structures of BSA within the complex particles. Preheating at 64 °C (below the irreversible stage of BSA thermodenaturation) leads to further enhancement in the complexation and formation of insoluble complexes stabilized by both Coulomb forces and hydrophobic interactions. The finding can be promising for the preparation of biodegradable BSA/chitosan-based drug delivery systems.