Enhanced and Heteromolecular Guest Encapsulation in Nonporous Crystals of a Perfluorinated Triketonato Dinuclear Copper Complex.

The flexible host framework of a perfluorinated mononuclear copper complex, [Cu(L1 )2 ] (1, HL1 =3-hydroxy-1,3-bis(pentafluorophenyl)-2-propen-1-one), with a CuO4 core reversibly encapsulated several organic guest molecules through electrostatic interactions in its crystals. Hence, the corresponding dinuclear complex, [Cu2 (L2 )2 ] (2, H2 L2 =1,5-dihydroxy-1,5-bis(pentafluorophenyl)-1,4-pentadien-3-one), was prepared to enhance guest recognition and the ability to separate molecular mixtures. Complex 2 comprises a Cu2 O6 core and four pentafluorophenyl groups. In crystal 2, cavities are formed on the axial sites of the metal core that are surrounded by pentafluorophenyl groups. The crystal of 2 encapsulates various guest molecules, that is, benzene (3), toluene (4), xylene (5), mesitylene (6), durene (7), and anisole (8). X-ray crystallographic and thermogravimetric (TG) studies show that three guest molecules are present in the crystal cavities. The number of guest molecules found in complex 2 was higher than that in complex 1, for example, (2)3 ⋅(6)10 >1⋅(6)2 , (2)2 ⋅(7)7 >1⋅7, or 2⋅(8)3 >1⋅(8)2 . Naphthalene (9), was encapsulated in 2 to give 2⋅(9)3 , but not in 1. In the crystal of complex 2, heteromolecular guest encapsulation was confirmed, designated as 2⋅(3)2 ⋅9. TG analysis indicates that the thermal stability of the guest-included crystals of 2 is higher than that of 1.

Fluorine-containing substituents: metabolism of the α,α-difluoroethyl thioether motif.

We report the metabolism of the recently introduced α,α-difluoroethyl thioether motif to explore further its potential as a substituent for bioactives discovery chemistry. Incubation of two aryl-SCF2CH3 ethers with the model yeast organism Cunninghamella elegans, indicates that the sulfur of the thioether is rapidly converted to the corresponding sulfoxide, and then significantly more slowly to the sulfone. When the substrate was (p-OMe)PhSCF2CH3, then the resultant (demethylated) phenol sulfoxide had an enantiomeric excess of 60%, and when the substrate was the ß-substituted-SCF2CH3 naphthalene, then the enantiomeric excess of the resultant sulfoxide was 54%. There was no evidence of defluorination, unlike the corresponding oxygen ether (p-OMe)PhOCF2CH3, which was converted to the (demethylated) phenol acetate ester during C. elegans incubation. We conclude that the aryl-S-CF2CH3 motif is metabolised in a similar manner to aryl-SCF3, a motif that is being widely explored in discovery chemistry. It is however, significantly less lipophilic than aryl-SCF3 which may offer a practical advantage in tuning overall pharmacokinetic profiles of molecules in development.

Fluoroalkyl Amino Reagents (FARs): A General Approach towards the Synthesis of Heterocyclic Compounds Bearing Emergent Fluorinated Substituents.

Fluorinated heterocycles are important building blocks in pharmaceutical, agrochemical and material sciences. Therefore, organofluorine chemistry has witnessed high interest in the development of efficient methods for the introduction of emergent fluorinated substituents (EFS) onto heterocycles. In this context, fluoroalkyl amino reagents (FARs)-a class of chemicals that was slightly forgotten over the last decades-has emerged again recently and proved to be a powerful tool for the introduction of various fluorinated groups onto (hetero)aromatic derivatives.

A transition-metal-free synthesis of fluorinated naphthols.

Herein, we describe a transition-metal-free protocol for the conversion of simple 2-allyl-3-(trifluoromethyl)phenols into substituted 5-fluoronaphthalen-1-ols. The key events of this reaction include the selective activation of two C-F bonds and formation of an intermediate hexatriene system, which undergoes a 6π electrocyclization, followed by rearomatization. This concept enables the rapid conversion (three steps) of various commercially available 3-(trifluoromethyl)phenols into novel fluorine-containing naphthols, which are difficult to prepare by previous methods. The reported sequence was also extended to a one-pot transformation of 3-(trifluoromethyl)phenols into 5-fluoronaphthalen-1-ols.

Regioselective hydroxylation of C(12)-C(15) fatty acids with fluorinated substituents by cytochrome†P450 BM3.

We demonstrate herein that wild-type cytochrome P450 BM3 can recognize non-natural substrates, such as fluorinated C12 -C15 chain-length fatty acids, and show better catalysis for their efficient conversion. Although the binding affinities for fluorinated substrates in the P450 BM3 pocket are marginally lower than those for non-fluorinated substrates, spin-shift measurements suggest that fluoro substituents at the ω-position can facilitate rearrangement of the dynamic structure of the bulk-water network within the hydrophobic pocket through a micro desolvation process to expel the water ligand of the heme iron that is present in the resting state. A lowering of the Michaelis-Menten constant (Km ), however, indicates that fluorinated fatty acids are indeed better substrates compared with their non-fluorinated counterparts. An enhancement of the turnover frequencies (kcat ) for electron transfer from NADPH to the heme iron and for CH bond oxidation by compound I (Cpd I) to yield the product suggests that the activation energies associated with going from the enzyme-substrate (ES state) to the corresponding transition state (ES(≠) state) are significantly lowered for both steps in the case of the fluorinated substrates. Delicate control of the regioselectivity by the fluorinated terminal methyl groups of the C12 -C15 fatty acids has been noted. Despite the fact that residues Arg47/Tyr51/Ser72 exert significant control over the hydroxylation of the subterminal carbon atoms toward the hydrocarbon tail, the fluorine substituent(s) at the ω-position affects the regioselective hydroxylation. For substrate hydroxylation, we have found that fluorinated lauric acids probably give a better structural fit for the heme pocket than fluorinated pentadecanoic acid, even though pentadecanoic acid is by far the best substrate among the reported fatty acids. Interestingly, 12-fluorododecanoic acid, with only one fluorine atom at the terminal methyl group, exhibits a comparable turnover frequency to that of pentadecanoic acid. Thus, fluorination of the terminal methyl group introduces additional interactions of the substrate within the hydrophobic pocket, which influence the electron transfers for both dioxygen activation and the controlled oxidation of aliphatics mediated by high-valent oxoferryl species.

Controlled oxidation of aliphatic CH bonds in metallo-monooxygenases: mechanistic insights derived from studies on deuterated and fluorinated hydrocarbons.

The control over the regio- and/or stereo-selective aliphatic CH oxidation by metalloenzymes is of great interest to scientists. Typically, these enzymes invoke host-guest chemistry to sequester the substrates within the protein pockets, exploiting sizes, shapes and specific interactions such as hydrogen-bonding, electrostatic forces and/or van der Waals interactions to control the substrate specificity, regio-specificity and stereo-selectivity. Over the years, we have developed a series of deuterated and fluorinated variants of these hydrocarbon substrates as probes to gain insights into the controlled CH oxidations of hydrocarbons facilitated by these enzymes. In this review, we illustrate the application of these designed probes in the study of three monooxygenases: (i) the particulate methane monooxygenase (pMMO) from Methylococcus capsulatus (Bath), which oxidizes straight-chain C1-C5 alkanes and alkenes to form their corresponding 2-alcohols and epoxides, respectively; (ii) the recombinant alkane hydroxylase (AlkB) from Pseudomonas putida GPo1, which oxidizes the primary CH bonds of C5-C12 linear alkanes; and (iii) the recombinant cytochrome P450 from Bacillus megaterium, which oxidizes C12-C20 fatty acids at the ω-1, ω-2 or ω-3 CH positions.