19F NMR study of intramolecular hydrogen bond of fluorine-containing compounds

Hydrogen bond is a kind of interaction widely existing in or between molecules, and its strength is between covalent interaction and van der Waals interaction, which is generally expressed as "X-H ·· Y", in which "··" represents hydrogen bond, X-H is hydrogen bond donor and Y is hydrogen bond receptor The most common classification of hydrogen bond is intermolecular hydrogen bond and intramolecular hydrogen bond At present, there are many methods to detect the types of hydrogen bond The formation of intramolecular hydrogen bonds can affect many physical and chemical properties of compounds, such as pKa, boiling point, solubility, etc., which can significantly improve the membrane permeability and three-dimensional space pre organization of molecules The introduction of hydrogen bonds into many drug molecules can improve the bioavailability of drugs Intramolecular hydrogen bonds have a very wide range of applications in the field of supramolecules IUPAC's definition of hydrogen bond (source: synthesis) fluorine atom has the largest electronegativity, strong electron binding of fluorine atom nucleus and low polarizability, which means that fluorine is a very weak hydrogen bond receptor In polar aprotic solvents, such hydrogen bonds are difficult to exist due to solvent competition, but intramolecular hydrogen bonds can be formed at low concentrations due to the advantage of space distance The Gibbs free energy of X-H ·· f is generally 1-4kcal / mol, which is a very weak hydrogen bond At present, there are many researches on C-F bond as hydrogen bond receptor Please refer to the review published by champagne and others on Synthesis (DOI: 10.1055/s-0034-1379537) Recently, Claudio from the University of Neuchatel in Switzerland Dalvit et al Studied the intramolecular hydrogen bond of 2-chloro-6-fluoro-n - (4-fluoro-1-methyl-1h-indazol-3yl) benzamide (1) in detail and systematically They found that the indazol ring fluorine atom and benzene ring fluorine atom can form hydrogen bond with amide N-H, and the hydrogen bond will lead to the coupling between fluorine and fluorine In order to avoid the influence of intermolecular hydrogen bond, the concentration of molecule (1) is very low (200 μ m) (a) The 19F NMR spectrum of molecule (1) (b) jf-f parameter experiment (source: Journal of fluorescence chemistry) From the above figure, we can find that the cleavage of indazol fluoride and phenyl fluoride is divided into two peaks There is a spatial coupling between F1 and F2, and there is a correlation between jf-f and the dielectric constant of the solvent The specific values are as follows: jf-f The relationship between coupling and solvent dielectric constant (source: Journal of fluorine chemistry) J f-f value increases with the increase of solvent dielectric constant, which is due to the degree of overlap between f-f space coupling and two fluorine atom lone pair electrons Generally, fluorine atom and fluorine atom will have electrostatic repulsion, solvent polarity will increase, repulsion will be weakened, and coupling constant will increase However, pure water as solvent does not conform to the law, because water is a good donor and acceptor of hydrogen bond, and it will compete with intramolecular hydrogen bond Molecule (1) has a rotatable amide structure, so it will produce many conformations The author has studied the kinetic phenomenon of molecule (1) by using NMR, and found that the two fluorine atoms in the same side molecule are more stable Rotatable amide structure (source: Journal of fluorine chemistry) the study of molecular conformation ratio by fluorine spectrum (source: Journal of fluorine chemistry) Summary: In short, the amide structure of the molecule can rotate freely, thus different conformations can be obtained When two fluorine atoms are on the same side, the intramolecular hydrogen bond of F ·· h ·· f will be formed The intramolecular hydrogen bond makes f and f adjacent, which can produce spatial coupling The coupling is greatly affected by solvents With the increase of dielectric constant, the f-f repulsion decreases and the coupling constant increases Intramolecular hydrogen bond has been widely used in drug materials and other fields Although the force is small, it has a huge impact on the structure and properties of molecules The nuclear magnetic resonance study of the micro behavior of intramolecular hydrogen bond has an important theoretical basis for explaining and predicting the properties of intramolecular hydrogen bond Article link: http:// RDOC = 1 &? FMT = High &? Origin = gateway &? Docanchor = & MD5 = b8429449ccfc9c30159a5f9aeaa92ffb