On the structure and torsional potential of trifluoromethoxybenzene: an ab initio and density functional study

Klocker, Johanna; Karpfen, Alfred; Wolschann, Peter

doi:10.1016/s0009-2614(02)01786-4

Cited by 41 publications

(50 citation statements)

References 25 publications

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“…Interestingly, similarly twisted conformations are also found for aryl‐bound difluoroalkyloxy groups. Spectroscopic studies and high‐level quantum‐mechanical calculations further show that preference for the planar arrangement in anisole (Δ E ∼3 kcal mol −1 ) is inverted to the orthogonal orientation in trifluoromethylanisole (Δ E ∼−0.5 kcal mol −1 ) 28…”

Section: The Effect Of a F Substituent On Molecular Conformationsupporting

confidence: 61%

Fluorine in Medicinal Chemistry

et al. 2004

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Fluorinated compounds are synthesized in pharmaceutical research on a routine basis and many marketed compounds contain fluorine. The present review summarizes some of the most frequently employed strategies for using fluorine substituents in medicinal chemistry. Quite often, fluorine is introduced to improve the metabolic stability by blocking metabolically labile sites. However, fluorine can also be used to modulate the physicochemical properties, such as lipophilicity or basicity. It may exert a substantial effect on the conformation of a molecule. Increasingly, fluorine is used to enhance the binding affinity to the target protein. Recent 3D-structure determinations of protein complexes with bound fluorinated ligands have led to an improved understanding of the nonbonding protein-ligand interactions that involve fluorine.

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Section: The Effect Of a F Substituent On Molecular Conformationsupporting

confidence: 61%

Fluorine in Medicinal Chemistry

et al. 2004

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“…This perpendicular preference is in good agreement with ab initio calculations that indicate a global minimum geometry at an aryl-O torsion angle of 90°. 78 The preference for an orthogonal arrangement for R ) CF 3 vs planar for R ) CH 3 can be rationalized by (i) the larger volume of the trifluoromethyl group leading to higher 1,4 strain in the planar conformation and (ii) electronic effects of the highly electronegative CF 3 group reducing the amount of π-conjugation of the oxygen ether atom with the aryl system (anomeric effect between oxygen lone pairs and C-F bonds).…”

Section: Substituted Aryl Systems -Stereoelectronic and Steric Effectsmentioning

confidence: 99%

Small Molecule Conformational Preferences Derived from Crystal Structure Data. A Medicinal Chemistry Focused Analysis

Brameld

Kuhn

Reuter

et al. 2008

J. Chem. Inf. Model.

333

332

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Based on torsion angle distributions of frequently occurring substructures, conformation preferences of druglike molecules are presented, accompanied by a review of the relevant literature. First, the relevance of the Cambridge Structural Database (CSD) for drug design is demonstrated by comparing substructures present in compounds entering clinical trials with those found in the CSD and protein-bound ligands in the Protein Data Bank (PDB). Next, we briefly highlight preferred conformations of elementary acyclic systems, followed by a discussion of sulfonamide conformations. Due to their central role in medicinal chemistry, we discuss properties of aryl ring substituents in depth, including biaryl systems and systems of two aryl rings connected by two acyclic bonds. For a subset of torsion motifs, we also compare torsion angle histograms derived from CSD structures with those derived from ligands in the PDB. Furthermore, selected properties of some six-and seven-membered ring systems are discussed. The article closes with a section on attractive sulfuroxygen contacts.

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“…This finding was also confirmed by MP4(SDTQ) computations. [40] It follows that there is almost free rotation in the initial compounds 5, which should increase the total energy by approximately 0.5 kcal/mol. Taking into account that the internal rotation should also effectively increase the energy of deprotonated 5 at position C (2) Ϫ by roughly 0.5 kcal/ mol, we can safely conclude that acidity of 5 should not be affected by rotational motion of the OCF 3 group.…”

Section: Koopmentioning

confidence: 96%

“…[37Ϫ40] The most sophisticated calculations were performed by Karpfen et al, [40] who found that the ortho [o]-conformation of OϪCF 3 group relative to the benzene plane is 0.5 kcal/mol more stable than the eclipsed [e]-conformation by MP2/cc-pVTZ and B3LYP/cc-pVTZ procedures. These conformations correspond to two minima on the potential surface, separated by a low barrier with a height of about 0.2 kcal/mol above the [e] conformation.…”

Section: Koopmentioning

confidence: 99%

Acidity of Substituted Benzenes − An Ab Initio Study of the Influence of Methoxy, Trifluoromethyl and Trifluoromethoxy Groups by a Novel Trichotomy Formula

Kovačević¹,

Maksić²,

Primorac³

2003

Eur J Org Chem

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Keywords: Acidity / Aromaticity / Electrostatic field effect / Substituent effectsThe acidities of mono-and polysubstituted benzenes incorporating one, two, or three OCH 3 , OCF 3 , or CF 3 groups were investigated by use of reliable ab initio theoretical models. The calculated deprotonation energies are in very good agreement with available experimental data, although these are unfortunately sparse. A recently developed novel trichotomy formula proved useful for interpretation of predicted variation in acidity in the monosubstituted compounds. In particular, the long-range final state effect in OCF 3 and CF 3 derivatives is confirmed. It is reflected in the stabilization of the lone-pair electrons formed upon deprotonation at the meta and para positions. The theoretically established long-

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On the structure and torsional potential of trifluoromethoxybenzene: an ab initio and density functional study

Cited by 41 publications

References 25 publications

Fluorine in Medicinal Chemistry

Fluorine in Medicinal Chemistry

Small Molecule Conformational Preferences Derived from Crystal Structure Data. A Medicinal Chemistry Focused Analysis

Acidity of Substituted Benzenes − An Ab Initio Study of the Influence of Methoxy, Trifluoromethyl and Trifluoromethoxy Groups by a Novel Trichotomy Formula

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