Understanding The Conformational Behaviour Of Ac-ala-nhme In Different Media. A Joint Nmr And Dft Study

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)The conformational behaviour of Ac-Ala-NHMe was studied in the gas-phase and in solution by theoretical calculations (B3LYP-D3/aug-cc-pVDZ level) and experimental H-1 NMR. The conformational preferences of this compound were shown to result from a complex interplay between the strengths of possible intramolecular hydrogen bonds, steric interactions, hyperconjugation, entropy effects and the overall dipole moments. The Ac-Ala-N(Me)(2) derivative was studied in addition, to design a system akin to Ac-Ala-NHMe, but with disrupted intramolecular hydrogen bonds involving the -NHMe group, mimicking the effect of polar protic solvents.133592069213EaStCHEMConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP [2011/01170-1, 2014/25903-6

The contribution of non-classical CHax∙∙∙OC hydrogen bonds to the anomeric effect in fluoro and oxa-methoxycyclohexanes

Authors thank FAPESP, CONFAP and The UK Academies FAPESP for a São Paulo International Research Collaboration (FAPESP #2019/05028-7). FAPESP is also gratefully acknowledge for an undergraduate fellowship to BAP (#2019/03855-3), and a Young Research Award to RAC (#2018/03910-1). CENAPAD-SP, CESUP and SDumont are acknowledged for computational resources used in the theory calculations. We also thank EPSRC for a grant (EP/S030506/1).In this theory study we demonstrate the dominance of non-classical 1,3-diaxial CHax∙∙∙OC hydrogen bonds (NCHBs) dictating a ‘pseudo‘ anomeric effect in selectively fluorinated methoxycyclohexanes and also influencing the axial preference in the classical anomeric exhibitor 2-methoxytetrahydropyran, a phenomenon which is most often described as a consequence of hyperconjugation. Analogues of methoxycyclohexane where ring CH2’s are replaced by CF2 can switch to an axial preference and theory methods (NBO, QTAIM, NCI) indicate the dominance of 1,3- CHax∙∙∙OMe interactions over hyperconjugation. For 2-methoxytetrahydropyran, it is revealed that the global contribution to the anomeric effect is from electrostatic interactions including NCHBs, not hyperconjugation, although hyperconjugation (nO→σ *CO or nO →σ*CC) remains the main contributor to the exo-anomeric phenomenon. When two and three ether oxygens are introduced into the ring, then both the NCHB interactions and hyperconjugative contributions become weaker, not stronger as might have been anticipated, and the equatorial anomers progressively dominate.PostprintPeer reviewe

Understanding the conformational behaviour of Ac-Ala-NHMe in different media. A joint NMR and DFT study.

The authors thank EaStCHEM, CNPq and FAPESP for the studentship (to R.A.C. #2011/01170-1, FAPESP), as is CNPq for the fellowship (R.R.).The conformational behaviour of Ac-Ala-NHMe was studied for the compound in the gas-phase and in solution by theoretical calculations and experimental 1H NMR. The conformational preferences of this compound showed to be resultant from a complex interplay between the strengths of possible intramolecular hydrogen bonds, steric interactions, hyperconjugation, entropy effects and the overall dipole moments. The Ac-Ala-N(Me)2 derivative was used in order to simulate the effect of polar protic solvents in disrupting intramolecular hydrogen bonds involving the -NHMe group in Ac-Ala-NHMe.PostprintPeer reviewe

2D Chemical Drawings Correlate to Bioactivities: MIA-QSAR Modelling of Antimalarial Activities of 2,5-Diaminobenzophenone Derivatives

Two-dimensional chemical structures of a series of 2,5-diaminobenzophenone derivatives, some farnesyltransferase inhibitors, have shown to correlate with the corresponding antimalarial activities. The descriptors in this QSAR analysis are pixels of the chemical structures (two dimensional images) transformed into binaries and, therefore, the data variance explaining the variance in the activities block corresponds to the coordinates of each pixel in each molecule. This method, named multivariate image analysis applied to quantitative structure-activity relationship (MIA-QSAR), was applied to model the antimalarial activities of the titled compounds and the results were compared to well known three-dimensional QSAR techniques for the same class of compounds. In addition to the simplicity and high predictive performance of the MIA-QSAR modelling, this 2D image-based method has the potential of working well when equally simple, classical analysis fails. Overall, the present QSAR analysis based on 2D chemical drawings (constrained structures) dispensed conformational screening and 3D alignment to provide a reliable QSAR model; the physicochemical description about e.g. steric effects and chiral centers is all contained in the way in which substituents in a congeneric series are drawn, and the method can serve as a tool to introduce those who are planning to deal with drug design

Inter- and intramolecular CF···C=O interactions on aliphatic and cyclohexane carbonyl derivatives

The authors thank EaStCHEM and the University of St Andrews for access to a computing facility managed by Dr H. Fruchtl., CNPq, and FAPESP for the studentship (to R.A.C. #2011/01170-1, FAPESP) and for financial support (#2014/25903-6), as well as CNPq for the fellowship (R.R.).The assessment of weak inter- and intra- molecular Cδ+Fδ-...Cδ+=Oδ- interactions were theoretically evaluated in 4 different sets of compounds at different theoretical levels. Intermolecular CH3F...C=O interactions were stabilizing by ca. 1 kcal mol-1 for various carbonyl containing functional groups. Intramolecular CF...C=O interactions were also detected in aliphatic and fluorinated cyclohexane carbonyl derivatives. However, the stabilisation provided by intramolecular CF...C=O interactions was not enough to govern the conformational preferences of compounds 2-4.PostprintPeer reviewe

Conformational analysis explores the role of electrostatic non-classical CFHC hydrogen bonding interactions in selectively halogenated cyclohexanes

Funding: Fundação de Amparo à Pesquisa do Estado de São Paulo - 2018/03910-1, 2023/14064-2; China Scholarship Council; Fundo de Apoio ao Ensino, à Pesquisa e Extensão, Universidade Estadual de Campinas - 3472/23The conformational equilibria of selectively halogenated cyclohexanes are explored both experimentally (VT-NMR) for 1,1,4,-trifluorocyclohexane 7 and by computational analysis (M06-2X/aug-cc-pVTZ level), with the latter approach extending to a wider range of more highly fluorinated cyclohexanes. Perhaps unexpectedly, 7ax is preferred over the 7eq conformation by ΔG = 1.06 kcal mol–1, contradicting the accepted norm for substituents on cyclohexanes. The axial preference is stronger again in 1,1,3,3,4,5,5,-heptafluorocyclohexane 9 (ΔG = 2.73 kcal mol–1) as the CF2 groups further polarize the isolated CH2 hydrogens. Theoretical decomposition of electrostatic and hyperconjugative effects by natural bond orbital analysis indicated that nonclassical hydrogen bonding (NCHB) between the C-4 fluorine and the diaxial hydrogens at C-2 and C-6 in cyclohexane 7 and 9 largely accounts for the observed bias. The study extended to changing fluorine (F) for chlorine (Cl) and bromine (Br) at the pseudoanomeric position in the cyclohexanes. Although these halogens do not become involved in NCHBs, they polarize the geminal −CHX– hydrogen at the pseudoanomeric position to a greater extent than fluorine, and consequent electrostatic interactions influence conformer stabilities.Peer reviewe

Particularly strong C-H...pi interactions between benzene and all-cis 1,2,3,4,5,6-hexafluorocyclohexane

The authors thank EaStCHEM and the University of St Andrews for access to a computing facility managed by Dr H. Fruchtl, CNPq and FAPESP for the studentship for R.A.C. (#2011/01170-1, FAPESP) and for financial support (#2014/25903-6), as well as CNPq for the fellowship for R.R. DO’H thanks the Royal Society for a Wolfson Research Merit Award.We present the first high-level ab initio benchmark study of the interaction energy between fluorocyclohexanes and benzene. These compounds form CH...pi interactions with aromatic solvents which causes notable shielding of the axial cyclohexane protons. For the recently synthesised all-cis 1,2,3,4,5,6-hexafluorocyclohexane the interaction energy with benzene amounts to -7.9 kcal/mol and -6.4 kcal/mol at the MP2 and SCS-MP2 levels, respectively (extrapolated to the complete basis set limit), which according to dispersion-corrected density functional calculations, is largely due to dispersion.PostprintPeer reviewe

Chiral ligands in hypervalent iodine compounds: synthesis and structures of binaphthyl-based λ3-iodanes

Several novel binaphthyl-based chiral hypervalent iodine(III) reagents have been prepared and structurally analyzed. Various asymmetric oxidative reactions were applied to evaluate the reactivities and stereoselectivities of those reagents. Moderate to excellent yields were observed, however, very low stereoselectivities were obtained. The NMR experiments indicate that these reagents are very easily hydrolyzed in either chloroform or DMSO solvents leading to limited stereoselectivities. It is concluded that the use of chiral ligands is an unsuccessful way to prepare efficient stereoselective iodine(III) reagents

Desenhos de estruturas químicas correlacionam-se com propriedades biológicas: MIA-QSAR

Descriptors in multivariate image analysis applied to quantitative structure-activity relationship (MIA-QSAR) are pixels of bidimensional images of chemical structures (drawings), which were used to model the trichomonicidal activities of a series of benzimidazole derivatives. The MIA-QSAR model showed good predictive ability, with r², q² and r val. ext.² of 0.853, 0.519 and 0.778, respectively, which are comparable to the best values obtained by CoMFA e CoMSIA for the same series. A MIA-based analysis was also performed by using images of alphabetic letters with the corresponding numeric ordering as dependent variables, but no correlation was found, supporting that MIA-QSAR is not arbitrary

Fluorine induced pseudo-anomeric effects in methoxycyclohexanes through electrostatic 1,3-diaxial interactions

Authors thank FAPESP, CONFAP and The UK Academies for a São Paulo International Research Collaboration (FAPESP #2019/05028-7). FAPESP is also gratefully acknowledge for an undergraduate fellowship to BAP (#2019/03855-3), and a Young Research Award to RAC (#2018/03910-1). The Chinese Scholarship Council (CSC) is thanked for a Studentship (CY). Finally CENAPAD-SP, CESUP and SDumont are acknowledged for computational resources used in theory calculations.We report counter‐intuitive axial preferences in non‐stereochemically biased, selectively fluorinated methoxycyclohexanes. These pseudo‐anomeric effects are apparent when electronegative CF2 groups are placed at the C‐2, C‐4 and C‐6 positions of the cyclohexane ring to render the C‐3/5 axial hydrogen atoms electropositive. The electrostatic interaction between these axial hydrogen atoms and the ‐OMe oxygen is stabilising. The effect is explored using high‐level ab initio and DFT calculations in the framework of NBO, QTAIM and NCI analysis across a range of derivatives, and experimentally (19F{1H}‐NMR at −80 °C) for some illustrative examples. The effect is significant in energy terms for a weak interaction, and illustrates a new stereoelectronic aspect attributed to selective fluorine substitution in organic chemistry.Publisher PDFPeer reviewe