Aliphatics direct fluorination

Dream reactions can be performed using chemical micro process engineering, e.g., via direct routes from hazardous elements [18]. The direct fluorination starting from elemental fluorine was performed both on aromatics and aliphatics, avoiding the circuitous Anthraquinone process. While the direct fluorination needs hours in a laboratory bubble column, it is completed within seconds or even milliseconds when using a miniature bubble column. Conversions with the volatile and explosive diazomethane, commonly used for methylation, have been conducted safely as well with micro-reactors in a continuous mode. 

Direct Fluorination of Aliphatics and Non-C Moieties The basic limitations of direct fluorinations are similar for aliphatic compounds as discussed already using the example of aromatic derivatives and so is the potential of microreactors. The fluorination of ethyl acetoacetate was carried out in an annular-flow microreactor. 

Scheme 2.4 Direct fluorination of aliphatic compounds in the tertiary position by an electrophilic mechanism [16].

Recent computational studies [23[ on the structure and charge distribution of hydrogen bonded F2 suggest a more differentiated view on the supposedly electrophilic mechanism of direct fluorination of aliphatic and aromatic hydrocarbons. Ab-initio calculations indicate that even for the complex of Fj with the extremely strong hydrogen-bond donor F3F as a model system, the energy of complex formation is very low - only 0.38 kcal mol (MP2/6-31+G //MP2/6-31+G level of theory, ZPE and BSSE correction) [24] (Scheme 2.9). Because of the low polarizabil-... 

Direct fluorination of Nli2 and NH groups in aliphatic compounds Difiuoroamine (difliiorimidc) NHF ... 

Related strategies have been successfully applied to the halogenation of aliphatic and aromatic C-H bonds. Yu reported iodination of alkyl chains attached to an oxazoline that binds the palladium catalysts (Equation 18.19a). In this iodination, the combination of PhI(OAc)j and are used as the reagents to effect iodination and oxidation. The use of directing groups on arenes has also made possible the regioselective halogenation of arenes. As illustrated by the catalyzed and uncatalyzed processes in Equation 18.19b, the palladium-catalyzed process can occur faster than the uncatalyzed process to form a product directed by the catalyst, rather than the electronic properties of the arene. Under microwave conditions, directed fluorination of arene C-H bonds can also occur (Equation 18.19c). ... 

Direct fluorination of aliphatics and non-C moieties Direct fluorination of benzenoid aromatics Direct fluorination of heterocyclic aromatics Oxidations of alcohols, diols and ketones with fluorine Photo-oxidation of a-terpinene and cyclopentadiene Oxidation of benzyl alcohol to benzaldehyde Homogeneously catalyzed oxidation of butyraldehyde Oxidation of sulfite to sulfate Photochlorination of aromatic isocyanates... 

The reactivities of the substrate and the nucleophilic reagent change vyhen fluorine atoms are introduced into their structures This perturbation becomes more impor tant when the number of atoms of this element increases A striking example is the reactivity of alkyl halides S l and mechanisms operate when few fluorine atoms are incorporated in the aliphatic chain, but perfluoroalkyl halides are usually resistant to these classical processes However, formal substitution at carbon can arise from other mecharasms For example nucleophilic attack at chlorine, bromine, or iodine (halogenophilic reaction, occurring either by a direct electron-pair transfer or by two successive one-electron transfers) gives carbanions These intermediates can then decompose to carbenes or olefins, which react further (see equations 15 and 47) Single-electron transfer (SET) from the nucleophile to the halide can produce intermediate radicals that react by an SrnI process (see equation 57) When these chain mechanisms can occur, they allow reactions that were previously unknown Perfluoroalkylation, which used to be very rare, can now be accomplished by new methods (see for example equations 48-56, 65-70, 79, 107-108, 110, 113-135, 138-141, and 145-146)... 

Aliphatic and aromatic nucleophilic substitutions with p Fjfluoride are usually performed either on an immediate precursor of the target molecule (direct labelling using a one-step process) or on an indirect precursor followed by one or more chemical steps leading to the target radiotracer. The first approach, if highly desirable, is in fact rarely practicable. The reaction conditions are often not compatible with the structure or with the various chemical functions borne by the radiopharmaceutical. It is therefore common that the radiosynthesis comprises at least two chemical steps first the introduction of fluorine-18 followed by what is often a (multi)deprotection step. It is not unusual either that fluorine-18 is first incorporated into a much simpler and chemically more robust molecule which is then coupled to a more sensitive entity under milder conditions, possibly still followed by a final deprotection step. Suchlike multi-step procedures are possible thanks to the favourable half-life of fluorine-18. However, the more complicated the process, the more chance of side reactions and complicated final purifications (see also Section 2.3), which may seriously hamper the automation of the process. 

Flexible aliphatic compounds are also selectively fluorinated. Such substrates may be alkanes, alcohols, carboxylic acid derivatives or ketones as long as the electron-withdrawing group is far enough from the reacting center (Table 2).44 There are differences in yields and reaction rates which are qualitatively easily understood and are directly related to the electron density of the reactive C —H bond. 

Both aromatic and aliphatic fluoroformates 7 can be readily prepared from phenols or alcohols and carbonyl difluoride and treated with sulfur tetrafluoride without isolation. Hydrogen fluoride evolved in the reaction of hydroxy compounds with carbonyl di fluoride serves as a catalyst for the consecutive reaction with sulfur tetrafluoride.15<)-162 This provides a general, convenient, direct synthesis of aryl and alkyl trifluoromethyl ethers 5 from phenols and alcohols. When the intermediate fluoroformate 7 is isolated prior to treatment with sulfur tetrafluoride, at least one mole equivalent of hydrogen fluoride is necessary to promote the fluorination reaction. 159 163 Representative examples of the conversion of hydroxy compounds 6 into trifluoromethyl ethers 5 via intermediate fluoroformates 7 are given (for other examples 7 -> 5, see Houben-Weyl, Vol. E4, pp 628. 629). 

Electrochemical fluorination 168,169> is a commercial process for perfluorina-tion of aliphatic compounds. The reaction is performed in liquid hydrogen fluoride -potassium fluoride at a nickel anode. The mechanism is not known free fluorine cannot be detected during electrolysis, so it seems probable that fluorination is a direct electrochemical reaction. Theoretically, hydrogen fluoride-potassium fluoride should be a very oxidation-resistant SSE, and it might well be that the mechanism is analogous to that proposed for anodic acetamidation of aliphatic compounds in acetonitrile-tetrabutylammonium hexafluorophosphate 44 K... 

Swelling resistance of fluoroelastomers is directly related to the fluorine content in the molecule. This is demonstrated by data in Table 5.3 [9]. For example, when the fluorine content is increased by mere 6% (from 65% to 71%), the volume swelling in benzene drops from 20% to 3%. Copolymers of VDF and HFP have excellent resistance to oils, fuels, and aliphatic and aromatic hydrocarbons, but they exhibit a relatively high swelling in low-molecular-weight esters, ketones, and amines, which is due to the presence of the VDF in their structure [10]. VDF-based fluoroelastomers... 

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