Fluorine Substitution Patterns Research Articles

Chemical Consequences of Fluorine Substitution. Part 4. Diels—Alder Reactions of Fluorinated p‐Benzoquinones with Dane′s Diene. Synthesis of Fluorinated D‐Homosteroids.

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Chemical consequences of fluorine substitution. Part 4. Diels–Alder reactions of fluorinated p-benzoquinones with Dane's diene. Synthesis of fluorinated D-homosteroids

Four fluorinated p-benzoquinones (2) have been reacted with Dane's diene (1) in Diels–Alder reactions and the formed fluorinated D-homosteroids were characterized. The number of products, their stereochemistry and stability depends on the fluorine substitution pattern of the corresponding fluorinated p-benzoquinones. If the p-benzoquinone (2) contains an unfluorinated double bond, this bond reacts faster with diene 1 yielding endo-products selectively. In contrast, [4+2]cycloadditions with 2,6-difluoro (2c) and 2,3,5,6-tetrafluorobenzoquinone (2d) gave the products with exo-orientation of the carbonyl part preferably.

Fluoroaromatic−Fluoroaromatic Interactions between Inhibitors Bound in the Crystal Lattice of Human Carbonic Anhydrase II

Intermolecular interactions of eleven different fluoroaromatic inhibitors are probed within the scaffolding of the crystal lattice of Phe-131-->Val carbonic anhydrase II. The degree and pattern of fluorine substitution on the inhibitor benzyl ring modulate its size, shape, and electronic character. In turn, these properties affect the geometry of intermolecular interactions between the fluoroaromatic rings of two different inhibitor molecules bound in the crystal lattice, as determined by X-ray crystallography. Depending on the degree and pattern of fluorine substitution, we observe a face-to-face (aromatic-aromatic) interaction, an atom-to-face (carbonyl-aromatic) interaction, or no interaction at all. These interaction geometries are analyzed with regard to van der Waals, electrostatic, and possible charge-transfer effects. For the aromatic-aromatic interactions investigated in this study, with aromatic ring quadrupoles specifically "tuned" by the degree and pattern of fluorination, the structural results suggest that London forces and charge-transfer complexation dominate over weakly polar electrostatic interactions in the association of aromatic ring pairs.

The pattern of fluorine substitution affects binding affinity in a small library of fluoroaromatic inhibitors for carbonic anhydrase.

[formula: see text] A library of fluoroaromatic inhibitors of carbonic anhydrase has been found to bind in a manner dependent on both hydrophobicity and the pattern of substitution of the fluoroaromatic ring. All of the compounds in the library bind to the protein with Kd < 3 nM. We have inferred two distinct binding modes from our data, which suggest two types of interactions that should be considered when designing fluorinated drugs.

How Do Different Fluorine Substitution Patterns Affect the Electronic State Energies of Phenylnitrene?

Substituted phenylnitrenes, reacting out of their closed-shellsinglet (CSS) states, can serve as photoaffinity labeling reagents if they engage in bond insertion reactions.1-3 Such reactivity is similar to that exhibited by singlet phenylcarbene.4 However, the reactivity of unsubstituted CSS phenylnitrene (PhN) is dominated by unimolecular ring expansion to form didehydroazepine.4,5 Substituents on the aromatic ring are required for bimolecular insertion reactions to compete with ring expansion, e.g., polyfluorinated phenylnitrenes, which were first examined by Banks and Prakash.6,7 Platz has demonstrated that the barrier to ring expansion in 2,6-difluorophenylnitrene ((o,oF2)PhN) is increased by 3-5 kcal/mol compared to unsubstituted PhN.4,8 Platz has also shown that proper location of the fluorines on the aromatic ring is critical to this effect; 3,5difluorophenylnitrene ((m,m-F2)PhN), like PhN, undergoes ring expansion faster than it participates in insertion reactions.2-4 Elucidating the energies for different electronic states of PhN has been the goal of several experimental9,10 and theoretical11-13 studies. Theory and experiment are in good agreement on the relative ordering of the lowest energy states. The ground state is a triplet (A2), the first excited state is an open-shell singlet (A2) lying about 18 kcal/mol higher in energy, and higher still is the first CSS (1A1). No experimental number is available for the relative energy of the latter state, but reasonable quality singleand multireference configuration interaction (CISD+Q) calculations place it 31-39 kcal/mol above the triplet. The electronic configuration of this state is dominated by double occupation of the nitrogen p orbital that lies in the plane of the aromatic ring. The next higher lying CSS (2A1) is derived from double excitation of that pair of electrons out of the inplane p orbital and into the aromatic π system. Kim et al.12 have estimated the energy of this state to be about 52 kcal/mol above the triplet, but the errors associated with this calculation may be substantial (vide infra). The energy of this state bears on the ring expansion reactivity of PhN insofar as it correlates with the CSS ground state of didehydroazepine, i.e., the ring expansion is a Wagner-Meerwein shift of a C-C bond to the electron-deficient nitrogen using the empty in-plane p orbital. On the basis of this analysis, Platz has speculated that different fluorine substitution patterns may preferentially stabilize the 1A1 state and hence lead to higher activation barriers for ring expansion.4 Of course, a more complete explanation includes the recognition that there must be an avoided crossing in the state-symmetry correlation diagrams, but the crux of the argument remains a differential effect on the relative energies of the two CSS states (Figure 1). In order to address this question, we have employed density functional theory14 (DFT) to calculate15,16 the relative energies of the triplet and CSS states of PhN, (o,o-F2)PhN, (m,m-F2)PhN, and 4-fluorophenylnitrene (p-FPhN) and their corresponding didehydroazepines. To assess the quality of this level of theory, we have compared the DFT results for PhN to multireference second-order perturbation theory (CASPT2N)17,18 employing an eight-electron/eight-orbital active space and also to single-reference coupled cluster19 calculations including all single, double, and perturbative triple20 excitations (CCSD(T)). These calculations are summarized in Table 1. The gap between the A2 and 1A1 states for PhN appears to be well predicted by DFT. On the basis of the results for methylene, Roos has suggested that the CASPT2N level overstabilizes triplets relative to singlets by 3-5 kcal/mol.21 Our own calculations for various carbenes and nitrenium ions have shown similar overstabilizations of triplet states by up to 8 kcal/ mol.22 The CCSD(T) calculations also support the DFT results. Because of the size of PhN, calculations at this level were not performed using a triple-u basis. The larger stabilization of the triplet at this level of theory compared to DFT is consistent with lesser flexibility in the basis set and the observed tendency of CCSD(T) to overstabilize triplets relative to CSSs by 1-2 kcal/mol in carbenes and nitrenium ions.22 Similar levels of DFT have previously been shown to accurately predict singlet-

Moth responses to selectively fluorinated sex pheromone analogs

Partially fluorinated analogs of the European corn borer (Ostrinia nubilalis) female sex pheromone, 11-tetradecenyl acetate (97:3Z:E), having mono- and trifluorsubstitutions at the terminal carbon of the pheromone chain, mimicked the biological activity of the pheromone, while analogs with fluorine at either side of the double bond and a pentafluoro analog were essentially inactive. Comparison of the pheromonal activity of these analogs with the previously reported activity of similarly fluorinated pheromones in five other species of moths revealed an unpredictable relationship between fluorine substitution pattern and pheromone-mimicking activity. Fluorine substitution patterns that rendered pheromonal analogs biologically inactive in the European corn borer had no detrimental influence upon pheromonal activity in other species and the converse was also true. This is evidence that the relative importance of electronic qualities of sites within a pheromone molecule differ from species to species. Furthermore, it indicates that the biochemical components (pheromone receptor proteins, binding proteins, and enzymes) that make up moth olfactory chemosensory systems must also vary structurally from species to species, despite the fact that they are involved in olfactory sensing of compounds having very similar chemical structure.

The vibrational force field of halogenated aromatic molecules: V. The CH stretching field in fluoroaromatics

It is shown that the average CH stretching frequencies in the fluoroaromatic series C 6H 6−nF n depend on the fluorine substitution patterns, being given by v̄ = v̄ B + n o X o + n m X m + n p X p. Two variants on the general quadratic force field, which are taken to be transferable between members of the series, have been fitted to the experimental data. Each ortho fluorine substituent increases the diagonal CH stretching force constant by 1.0%. The dependence on meta and para substituents is not as obvious as with the average stretching frequency due to the rather large variance. A comparison with existing correlations between average stretching frequencies and bond length data indicates that an ortho fluorine atom leads to a CH bond shortening of 0.0017 A. Such information could prove of value in microwave structural investigations.