Stereoelectronic interactions are too weak to explain the molecular conformation in solid state of cis-2-tert-butyl-5-(tert-butylsulfonyl)-1,3-dioxane.

cis-2-tert-Butyl-5-(tert-butylsulfonyl)-1,3-dioxane (cis-1) exhibits a high degree of eclipsing in the H-C5-S-C segment in the solid state, the origin of which remains unexplained. The eclipsed conformation that corresponds to an energetic minimum in the solid state practically corresponds to a rotational transition state in solution, which allows an approach to understand transitions states. The difference in the enthalpy of sublimation ΔsubH between cis-1 and the more stable trans-1 is 8.40 kcal mol-1, lets to consider that the intermolecular interactions in the crystalline structure must be responsible for the conformational effect observed in the solid state. The study of the experimental electron density of cis-1 in solid state allowed to establish that CH⋯OS intermolecular interaction is the main contribution to the observed eclipsing. The charge density analysis was also performed using the quantum theory of atoms in molecules to evaluate the nature and relevance of the intermolecular interactions in the crystal structure.

Harnessing the Reactivity of Duclauxin toward Obtaining hPTP1B1-400 Inhibitors.

Duclauxin (1) from Talaromyces sp. IQ-313 was reported as a putative allosteric modulator of human recombinant protein tyrosine phosphatase 1B (400 amino acids) (hPTP1B1-400), a validated target for the treatment of type II diabetes. Based on these findings, a one-strain-many-compound (OSMAC) experiment on the IQ-313 strain generated derivatives 5a, 6, and 7. Moreover, a one-/two-step semisynthetic approach guided by docking toward hPTP1B1-400 produced 38 analogs, a series (A) incorporating a lactam functionalization at C-1 (8a-15a, 36a, and 37a) and a series (B) containing a lactam at C-1 and an extra unsaturation between C-7 and C-8 (5b, 11b-37b). In vitro evaluation and structure-activity relationship (SAR) analysis revealed that analogs from the B series are up to 10-fold more active than 1 and derivatives from the A series. Furthermore, duclauxin (1) and 36b were assessed for their potential acute toxicity, estimating their LD50 to be higher than 300 mg/kg. Moreover, 36b significantly reduced glycemia in an insulin tolerance test in mice, suggesting that its mechanism of action is through the PTP1B inhibition.

How solvent determines the molecular reactive conformation and the selectivity: Solvation spheres and energy.

In solution, the solvent determines the molecular conformation and the chemical reaction viability and selectivity. When solvent-solute and solvent-solvent interactions present similar strengths, explicit salvation is the best way to describe a system. The problem to solve is how big the explicit shell should be. In this paper, we want to answer one of the fundamental questions in the implementation of explicit solvation, exactly how many solvent molecules should be added and where they should be placed. Here we determine the first solvent sphere around a molecule and describe how it controls the conformation and selectivity of a selected reaction. NMR experiments were carried out to identify the number of solvent molecules around the solute that constitutes the first solvent sphere, and the interaction between this solvent sphere and the solute was detected using DFT and QTAIM calculations. A new approach to the solvation energy is presented. Finally, we established the role of solvent molecules in the conformation of the solute and in the transition states that produce the two possible products of the reaction.

Effect of the nO → π*C═O Interaction on the Conformational Preference of 1,3-Diketones: A Case Study of Riolozatrione Derivatives.

The cyclopropane ring-opening reaction of riolozatrione, a natural product obtained from Jatropha dioica, afforded a 2,2-disubstituted 1,3-cyclohexandione displaying an alkyl methyl ether group at position 5. The conformational analysis of this product showed a high preference for the trans-diaxial conformation in both solution and solid state. Such conformation was possible from the noncovalent intramolecular nX → π*C═O interactions (X = an element having an unshared electron pair), allowing the determination of the interaction energies. Since the nX → π*C═O interactions can be regarded as additive, the energy values ranged from 4.52 to 6.51 kcal mol-1 for each carbonyl group with a strong dependency on the interatomic distances. The rigorous analysis of the electron density in the topological theory of atoms in molecules framework clearly shows that the origin of O-C═O interactions are through the nO → π*C═O electron transfer mechanism. Such interactions are slightly weaker than a canonical hydrogen bond but seemingly stronger than a van der Waals interaction. This interaction must be considered as a stereoelectronic effect due the electronic transfer between the interacting groups, which are limited by their relative stereochemistry and can be represented by a bond-no bond interaction, causing the pyramidalization of the carbonyl, which is the charge acceptor group.

Acidity and basicity interplay in amide and imide self-association.

Amides dimerise more strongly than imides despite their lower acidity. Such an unexpected result has been rationalised in terms of the Jorgensen Secondary Interactions Hypothesis (JSIH) that involves the spectator (C[double bond, length as m-dash]OS) and H-bonded (C[double bond, length as m-dash]OHB) carbonyl groups in imides. Notwithstanding the considerable body of experimental and theoretical evidence supporting the JSIH, there are some computational studies which suggest that there might be other relevant intermolecular interactions than those considered in this model. We conjectured that the spectator carbonyl moieties could disrupt the resonance-assisted hydrogen bonds in imide dimers, but our results showed that this was not the case. Intrigued by this phenomenon, we studied the self-association of a set of amides and imides via 1H-NMR, 1H-DOSY experiments, DFT calculations, QTAIM topological analyses of the electron density and IQA partitions of the electronic energy. These analyses revealed that there are indeed repulsions of the type OS···OHB in accordance with the JSIH but our data also indicate that the C[double bond, length as m-dash]OS group has an overall attraction with the interacting molecule. Instead, we found correlations between self-association strength and simple Brønsted-Lowry acid/base properties, namely, N-H acidities and C[double bond, length as m-dash]O basicities. The results in CDCl3 and CCl4 indicate that imides dimerise less strongly than structurally related amides because of the lower basicity of their carbonyl fragments, a frequently overlooked aspect in the study of H-bonding. Overall, the model proposed herein could provide important insights in diverse areas of supramolecular chemistry such as the study of multiple hydrogen-bonded adducts which involve amide or imide functional groups.

Transformations in Chemically Responsive Copper-Calixarene Architectures.

Self-assembly of bis-picolyl-appended calix[4]arene (L) with CuI or CuII salts resulted in a collection of multinuclear architectures capable of expressing structural reconfigurations in response to various chemical stimuli: addition of copper salt, solvents, or oxidation. Coordination of L to CuX (X=Br, I) selectively yielded dinuclear macrocycles CuI2 L2 Br2 (1) and CuI2 L2 I2 (3) that were transformed into tetranuclear assemblies CuI4 L2 Br4 (2) and CuI4 L2 I4 (4) upon further addition of CuX. These supramolecules persist as robust and discrete entities in solution that display red emission; notably, 4 exhibits luminescence thermochromism. Assembly of L with CuCl2 produced macrocycle CuII2 L2 Cl4 (5), which crystallised as cage [CuII2 L4 (µ-Cl)]3+ (6) in the presence of MeOH. Two chemical signals-introduction of CuCl2 and addition of CH3 CN-regenerated macrocycle 5. Coordination of L to Cu(OTf) yielded macrocycle CuI2 L2 (OTf)2 (7) that also crystallised as cage 6 upon oxidation in CHCl3 .

Supramolecular fluorescence enhancement via coordination-driven self-assembly in bis-picolylcalixarene blue-emitting M2L2Xn macrocycles.

The lower-rim functionalised distal bis-(4-picolyl)-p-tert-butylcalix[4]arene () selectively and quantitatively self-assembles into a series of discrete [2 + 2] blue-emitting metallacycles of general formula M2L2Xn with diverse metal salts (M = Zn(2+), Pd(2+), Ag(+), and Cd(2+); X = Cl(-), NO3(-), ClO4(-), BF4(-) , CF3SO3(-), PF6(-), SbF6(-); n = 2, 4). Macrocycle assembly has been corroborated by 2D-DOSY NMR and ESI-MS analyses, which further indicate that the M2L2Xn entities are quite stable and persist as robust and discrete macrocyclic species in solution. While free units display modest blue emission (λmax = 307-405 nm), self-assembly of M2L2Xn results in amplified fluorescence (up to 13-fold). This remarkable enhancement may be primarily ascribed to the increase in conformational rigidity imposed on the units by supramolecular assembly formation upon metal coordination to the pyridyl groups; in addition, subtle intensity-emission modulation may be provided by the different metal components. Titrations aimed at exploring the possibilities for ratiometric detection of metal cations or sensing of nitroaromatic species, revealed that the M2L2Xn platform may be a suitable "turn-on/off" system. Our results provide valuable insights into luminescence enhancement within the context of coordination-driven assemblies, which may be engineered to increase their fluorescence by imposing rigidity on the chromophores.

Conformational properties of the germacradienolide 6-epidesacetyllaurenobiolide by theory and NMR analyses.

Knowing the conformational properties of 1(10),4-cyclodecadiene gamma-lactones is important because of the biogenetic and evolutionary implications on the different groups of sesquiterpene lactones. Despite their importance, there are no physicochemical data on the conformational dynamic and the potential energy surface associated with the conformational changes of the cyclodecadiene ring. Fischer's biogenetic theory on the origin of ambrosanolides and helenanolides has support in the results presented since the conformers that yield two groups of sesquiterpene lactones coexist in solution as demonstrated by dynamic NMR experiments. These results are important on the basis of Fischer's proposal that states that the biosynthesis of each group of pseudoguaianolides requires a specific enzyme to select the right conformer to start the electrophilic cyclization. The germacra-1(10),4-dien-12,8alpha-olides can exist as a mixture of four different conformations, [(15)D(5),(1)D(14)], [(15)D(5),(1)D(14)], [(15)D(5),(1)D(14)], and [(15)D(5),(1)D(14)], and it is also proposed that the configuration of trans-annular cyclization depends on the conformation of the precursor. The results of the study presented herein show that 6-epi-desacetyllaurenobiolide exists in solution at room temperature as a mixture of two stable conformers, [(15)D(5),(1)D(14)] and [(15)D(5),(1)D(14)], which are more stable due to the diminishing of the so-called allylic strain. Analysis of the potential energy surface associated with the conformational interchange showed two other conformers that are intermediaries in the equilibria between [(15)D(5),(1)D(14)]/[(15)D(5),(1)D(14)] and [(15)D(5),(1)D(14)]/[(15)D(5),(1)D(14)]. This indicates the presence of six different conformers participating in the global process instead of the four that have been proposed. The experimental values of DeltaH(++), DeltaG(++), DeltaH(conf), and DeltaG(conf) of the conformational exchange and those calculated at the mPW1B95/6-31+G(d,p) level of theory are very similar, indicating that such level of theory is adequate for the description of this conformational equilibrium.

Enthalpic nature of the CH/pi interaction involved in the recognition of carbohydrates by aromatic compounds, confirmed by a novel interplay of NMR, calorimetry, and theoretical calculations.

Specific interactions between molecules, including those produced by a given solute, and the surrounding solvent are essential to drive molecular recognition processes. A simple molecule such as benzene is capable of recognizing and differentiating among very similar entities, such as methyl 2,3,4,6-tetra-O-methyl-alpha-D-galactopyranoside (alpha-Me(5)Gal), methyl 2,3,4,6-tetra-O-methyl-beta-D-galactopyranoside (beta-Me(5)Gal), 1,2,3,4,6-penta-O-acetyl-beta-D-galactopyranose (beta-Ac(5)Gal), and methyl 2,3,4,6-tetra-O-methyl-alpha-D-mannopyranoside (alpha-Me(5)Man). In order to determine if these complexes are formed, the interaction energy between benzene and the different carbohydrates was determined, using Calvet microcalorimetry, as the enthalpy of solvation. These enthalpy values were -89.0 +/- 2.0, -88.7 +/- 5.5, -132.5 +/- 6.2, and -78.8 +/- 3.9 kJ mol(-1) for the four complexes, respectively. Characterization of the different complexes was completed by establishing the molecular region where the interaction takes place using NMR. It was determined that beta-Me(5)Gal is stabilized by the CH/pi interaction produced by the nonpolar region of the carbohydrate on the alpha face. In contrast, alpha-Me(5)Man is not specifically solvated by benzene and does not present any stacking interaction. Although alpha-Me(5)Gal has a geometry similar to that of its epimer, the obtained NMR data seem to indicate that the axial methoxy group at the anomeric position increases the distance of the benzene molecules from the pyranose ring. Substitution of the methoxy groups by acetate moieties, as in beta-Ac(5)Gal, precludes the approach of benzene to produce the CH/pi interaction. In fact, the elevated stabilization energy of beta-Ac(5)Gal is probably due to the interaction between benzene and the methyl groups of the acetyls. Therefore, methoxy and acetyl substituents have different effects on the protons of the pyranose ring.

Calorimetric measurement of the CH/pi interaction involved in the molecular recognition of saccharides by aromatic compounds.

Can a benzene molecule differentiate between two isomeric carbohydrates? It is generally accepted that two factors govern molecular recognition: complementarity and preorganization. Preorganization requires the presence of cavities for positioning the host's groups of complementary nature to those of the guest. This study shows that, in fact, groups should be complementary to recognize each other (for the case presented here, it is controlled by the CH/pi interaction) but preorganization is not essential. Since weak interactions have their origin in dispersion forces, they also have impact on the enthalpic term of the free energy, so it was considered that their participation can be demonstrated by measuring the energy involved. For recognition to happen, two conditions must be satisfied: specificity and associated stabilizing energy. In this study we evaluated the heat of dissolution of different carbohydrates such as methyl 2,3,4,6-tetra-O-methyl-alpha-d-mannopyranoside and methyl 2,3,4,6-tetra-O-methyl-beta-d-galactopyranoside using different aromatic solvents. The solvation enthalpies in benzene were -78.8 +/- 3.9 and -88.7 +/- 5.5 kJ mol(-1) for each carbohydrate, respectively; and these values yielded a CH/pi energy of interaction of 9.9 kJ mol(-1). In addition, NMR studies of the effect of the addition of benzene to chloroform solutions of the two carbohydrates showed that benzene specifically interacts with the hydrogen atoms of the pyranose ring at positions 3, 4, and 5 located on the alpha face of the methyl-beta-galactoside, so it is, in fact, able to recognize it. Thus, the interactions between carbohydrates and the aromatic residues of proteins occur in the absence of the confinement generated by the protein structure. By experimentally measuring the energy associated with this interaction and comparing it to theoretical calculations, it was also possible to unequivocally determine the existence of CH/pi interactions between carbohydrates and proteins.