Fluorination hydrolytic

Hydrolytic cleavage of single carbon-fluorine bonds generally requires activation by a neighboring group such as a carbonyl, sulfonyloxy, or olefinic bond or a negatively substituted aromatic group. 

Physicochemical Impact of Fluorine Substitution on Hydrolytic Processes... 

The usual order found with halogenonitrobenzenes is F > Cl Br I, the order of Cl and Br being variable, just as in heteroaromatic reactivity. The position of fluorine is of interest the available data indicate that it is usually the same as for nitrobenzene derivatives. Thus, in acid hydrolysis the order F > Cl for 2-halogeno-quinolines can be deduced beyond doubt since the fluoro derivative appears to react in the non-protonated form and the chloro derivative to resist hydrolytic attack even in the protonated form under appropriate conditions (Section II,D, l,d). Furthermore, in the benzo-thiazole ring, fluorine is displaced by the CHgO reagent at a rate 10 times that for chlorine. ... 

Phosphazene polymers can act as biomaterials in several different ways [401, 402,407]. What is important in the consideration of skeletal properties is that the -P=N- backbone can be considered as an extremely stable substrate when fluorinated alcohols [399,457] or phenoxy [172] substituents are used in the substitution process of the chlorine atoms of (NPCl2)n> but it becomes highly hydrolytically unstable when simple amino acid [464] or imidazole [405-407] derivatives are attached to the phosphorus. In this case, an extraordinary demolition reaction of the polymer chain takes place under mild hydrolytic conditions transforming skeletal nitrogen and phosphorus into ammonium salts and phosphates, respectively [405-407,464]. This opens wide perspectives in biomedical sciences for the utilization of these materials, for instance, as drug delivery systems [213,401,405,406,464] and bioerodible substrates [403,404]. 

The metabolism of fluorobenzoates has been examined over many years. Early studies using Nocardia erythropoUs (Cain et al. 1968) and Pseudomonas fluorescens (Hughes 1965) showed that although the rates of whole-cell oxidation of fluorobenzoates were less than for benzoate, they were comparable to, and greater than for, the chlorinated analogs. As for their chlorinated analogs, both dioxygenation and hydrolytic pathways may be involved, and studies have revealed that the different pathways depended on the positions of the fluorine substituents. 

For the 4-fluorinated compounds, loss of fluoride may take place hydrolytically before ring fission. 

The metabolism of pentafluoro-, pentachloro-, and pentabromophenol by Mycobacterium fortuitum strain CG-2 is initiated by a monooxygenase that carries out hydroxylation at the para position (Uotila et al. 1992). Cell extracts of Rhodococcus chiorophenoiicus Mycobacterium chlorophenolicunt) strain PCP-1 in the presence of a reductant transformed tetrafluoro-, tetrachloro-, and tetrabromohydroquinone to 1,2,4-trihydroxybenzene by reactions that clearly involve both hydrolytic and reductive loss of fluorine (Uotila et al. 1995). 

Wholly aromatic polymers are thought to be one of the more promising routes to high performance PEMs because of their availability, processability, wide variety of chemical compositions, and anticipated stability in the fuel cell environment. Specifically, poly(arylene ether) materials such as poly-(arylene ether ether ketone) (PEEK), poly(arylene ether sulfone), and their derivatives are the focus of many investigations, and the synthesis of these materials has been widely reported.This family of copolymers is attractive for use in PEMs because of their well-known oxidative and hydrolytic stability under harsh conditions and because many different chemical structures, including partially fluorinated materials, are possible, as shown in Figure 8. Introduction of active proton exchange sites to poly-(arylene ether) s has been accomplished by both a polymer postmodification approach and direct co-... 

The structurally similar clofarabine is also marketed for the treatment of leukaemia [97]. The fluorine substitution at 2 increases the hydrolytic stability of the drug. Because of its electronegative character, fluorine disfavours the development of positive charge on the anomer carbon, required for the hydrolytic cleavage of nucleosides (see Section 2.3.2.) (Fig. 34) [2, p. 92]. 

This beneficial effect of fluorination on hydrolytic stability has also been demonstrated with the synthetic prostaglandin SC-46275 (Fig. 70). This compound possesses an anti-secretory activity that protects the stomach mucous membrane. However, its clinical development was too problematic because of the instability of the tertiary allyl alcohol in acidic medium (epimerisation, dehydration, etc.). A fluorine atom was introduced on the C-16 methyl to disfavour the formation of the allylic carbocation. This fluorinated analogue possesses the same biological activity, but does not undergo any degradation or rearrangement, and itepimerises only slowly [165]. 

The presence of fluorine strongly destabihzes a carbocation centered on the jS carbon because only the inductive effect takes place. " The effect on solvolysis or protonation reaction of double bonds can be very important. The destabilization of carbenium and alkoxycarbenium ions plays an importantrole in the design of enzyme inhibitors (cf Chapter 7) and in the hydrolytic metabolism of active molecules (cf. Chapter 3). 

The introduction of fluorine atoms in a molecule can be used to modify the processes and the rates of metabolism of the drug, in order to extend the plasma half-life or avoid the formation of toxic metabolites. Due to the properties of the fluorine atom, in particular its electronic effects, it may interact differently during the biotransformation steps, according to the type of processes involved (oxidative, reductive, hydrolytic, etc), which allow the clearance of the exogen molecule (i.e., the elimination of the active substance from the organism). 

Figure 3.18 Enhancement of the hydrolytic stability of prostaglandin derivatives by fluorination. ...

Fluorination of the aminoglucoside fragment has also been performed to increase its hydrolytic stability (Figure 4.62). Although some compounds reached a preclinical... 

These effects result from the impact of fluorination on the properties of the peptide at the level of (1) the lipophilicity/hydrophobicity balance and p faJ (2) the conformation, because of the more demanding volume of the fluorinated moiety and (3) the hydrolytic and metabolic stability. 

The effects of the presence of a fluorinated amino acid on the activity of these peptides are changeable the activity can be maintained, enhanced, or lowered the effect can be that of an agonist or antagonist. However, often the biological effect is enhanced, while the affinity is lowered. The loss of affinity is compensated by an increased biodisponibility due to the better hydrolytic and metabolic stability of the polypeptide that contains the fluorinated amino acid. 

By far, 2-fluoro-2-deoxyfuranoses have been the most studied compounds. Indeed, at a structural level they are the closest analogues of 2-deoxynucleosides. Due to its electronic effect, the fluorine atom in the 2 position inhibits development of a positive charge on the anomeric carbon (which is responsible for the hydrolytic cleavage of nucleosides). In order to enhance the stability of 2-deoxynucleosides in acidic medium, and thus make oral administration of an antiviral compound easier, introduction of a fluorine atom in the 2 position is a commonly used strategy. The resulting protective effect toward proteolysis has been well demonstrated, as exemplified by the fluorinated analogues of ddl and ddA (cf. Chapter 3, Figure 3.13). However, the presence of this fluorine atoms often induces modifications in the antiviral properties of the molecule. ... 

Fluorofuranose precursors are prepared via Horner-Emmons reaction on L-glyceraldehyde acetonide (Figure 6.11). Due to the allylic position of the base, these compounds are much more unstable than the related saturated molecules (cf. Figure 3.17, Chapter 3). The presence of the fluorine atom enhances the hydrolytic stability of these compounds. Some of these molecules have good antiviral activities on infected cells. 

Trifluoromethyl /1-thioalkyls and /1-amino alcohols are often good reversible inhibitors of esterases and proteases, respectively. Depending on the enzymes (serine or aspartyl enzymes), fluorinated alcohols are often less efficient inhibitors than the corresponding ketones, which act as analogues of the transition state (vide infra). Nevertheless, fluoroalcohols inhibit hydrolytic enzymes with high inhibition constants (Figure 7.25)." ... 

The comparatively simple method of preparation of tetrakis (trifluorophos-phine)nickel-(0) encouraged some scouting experiments on its still unexplored chemistry. Whereas the compound is hydrolytically remarkably stable, it was found to react readily with amines and ammonia with complete aminolysis of the phosphorus-fluorine bonds. Very typical of tetrakis(trifluorophosphine) nickel-(0) and similar fluorophosphine and chlorophosphine complexes of zerovalent nickel is the rapid decomposition with precipitation of elemental nickel by aqueous alkali hydroxide. 

One of the more important and promising groups is comprised of the pendant polyesters, which can be fluorinated as in example a and preserve up to 80% of the ester linkages. Of ester linkages that do decompose, most end up as acid fluorides directly. The perfluoroesters are extremely hydrolytically unstable and are easily hydrolyzed to give the perfluoro acids. Specific examples of... 

Due to their industrial applications, tetrafluorooxirane and perfluoro(2-methyloxirane) are the most frequently mentioned epoxides in the literature, and a number of methods have been developed for their synthesis. Although the epoxidation of perfluoroalkenes with hydrogen peroxide in alkaline media appears to be the most general method for the synthesis of per-fluorinated epoxides, it cannot be used in the preparation of tetrafluorooxirane due to the hydrolytic decomposition of the alkene. 

Hydrolytic replacement of a fluorine attached to a C = C bond by a hydroxy group leads to the hydroxy compound or its tautomeric carbonyl compound. For example, 2,3,3,4,4,4-hexa-fluoro-l-(phenyldiazenyl)but-l-ene (7) is hydrolyzed in acidic media to give the phenyl-hydrazone in a mixture with its tautomer.13... 

Hydrolytic fission of a carbon chain which occurs with a,a,a-trihalo carbonyl compounds and which affords haloforms is observed with certain fluorinated compounds. Although R3C —F bonds are not broken, it is convenient to mention the process here. A special example is the hydrolysis of hexafluoro-2-phenylpropan-2-ol (5) in which two moles of trifluoromethane are liberated. 73... 

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