Geminal, hydrolysis

Hydrolysis of geminal fluorides requires activation by per- or polyfluoroalkyl or perfluoroaryl groups and by double bonds linked to the same or adjacent carbon The activation is the result of reducing the electron density at the fluorinated carbon, facilitating attack by, primarily, nucleophilic reagents... 

Some small-ring compounds containing geminal fluorines suffer hydrolysis of fluorine only after initial opening of the ring For example, alkaline hydrolysis of... 

The most important example to be discussed here is that of the drug chloramphenicol (11.39, R = 2-hydroxy-l-(hydroxymethyl)-2-(4-nitrophen-yl)ethyl, Fig. 11.7), the many metabolic pathways of which have yielded a wealth of information [75], The dichloroacetyl moiety is especially of interest in that dechlorination proceeds by three proven routes glutathione-dependent dechlorination, cytochrome P450 catalyzed oxidation, and hydrolysis. Of particular value is that the oxidative and hydrolytic routes can be unambiguously distinguished by at least one product, as shown in Fig. 11.7. Oxidation at the geminal H-atom produces an unstable (dichloro)hydroxyacet-amido intermediate that spontaneously eliminates HC1 to yield the oxamoyl... 

The )>-form(IV) has so far remained elusive. The rate of tautomerisation is proposed as playing a key role in determining the hydrolysis pathway. Thus, if the rate of tautomerisation is slower than the subsequent hydrolysis, nucleophilic attack at the same phosphorus leads to a geminal dihydroxy derivative. This undergoes tautomerisation to give a hydroxy oxophosphazadiene. Alternatively faster tautomerisation leads to nongeminal attack (Scheme 11) [154]. 

Cumulenes such as butatrienes and hexapentaenes can undergo cycloaddition at several possible double-bond sites. The electrophilic l,l-diphenyl-4,4-bis(trifluoromethy )butatriene (34), however, reacts with ketene acetals and geminal enediamines at the central double bond exclusively.25 In the case of the ketene acetal cycloadduct 35 (R1 = H R2 = R3 = OMe). acid-catalyzed hydrolysis gives the cyclobutanone. 

Acidic media favor the hydrolysis, and alkaline reagents, usually, but not without exceptions,141 142 do not attack geminal difluorides. Thus, perfluorocyclobutene with potassium hydroxide gives trifluoro-3-hydroxycyclobut-2-enone derivative 3.142... 

Attempts to brominate the free amine (148) were disappointing (Scheme 3.28). Either incomplete reaction was observed or else a mixture of mono-, di- and tribrominated compounds was obtained. Nonetheless, treatment of this crude mixture with p - am i n o b en z oy lglutam ic acid generated the amide (149), which presumably resulted from bromide displacement in the tribromomethyl precursor, followed by hydrolysis of the remaining geminal dibromide during work-up. 

We showed in Figs. 3-2 and 3-3 that the tetrahedral intermediate which is initially formed from the reaction of a nucleophile with a carbonyl compound may further react in a number of different ways. In this section, we will consider some reactions which proceed along the pathway indicated in Fig. 3-3. The hydration of ketones is a reaction analogous to the hydrolysis of an ester, with the first step of the reaction involving nucleophilic attack of water on the carbonyl group. The tetrahedral intermediate is trapped by reaction with a proton to yield the hydrated form of the ketone, the geminal diol (Fig. 3-15). Similar reactions occur with alcohols as nucleophiles to yield, initially, hemiacetals. 

The first step in the hydrolysis in tert-butyl alcohol is probably nucleophilic displacement of fluorine in the reactive allylic position. Spontaneous elimination of hydrogen fluoride from the geminal fluorohydroxy compound yields perfluorocyclopent-2-en-l-one. 

The reaction in Explanation 43 is not a typical hydrolysis of geminal difluorides. A simple example of hydrolysis of geminal difluorides is conversion of 1,1-difluorocyclohexane to cyclohexanone. It is not easy, and takes place in alkaline or acidic media under very energetic conditions [66],... 

Scheme 10. Reaction sequence for the synthesis of tri-, tetra-, and penta(isopropyl)cyclo-pentadienes (34,35) from di(isopropyl)-Cp (59) via a series of metallations/alkylations. Tri(isopropyl)-Cp is obtained in a 4 1 mixture of the 1,2,4- and 1,2,3-substituted isomers. The C—H acidic tetra(isopropyl) isomers are separated from the 5,5 -geminal dialkylated forms by their transformation in the sodium salt and evaporation of the nonmetallated components. Subsequent hydrolysis yields l,2,3,4-tetra(isopropyl)cyclopentadiene in an iso-merically pure form. Similarly, l,2,3,4,5-penta(isopropyl)-Cp is purified after separation of the 1,2,3,S,5 derivative as the main alkylation product. For more details and the respective yields, see Refs. 34 and 35.

A large number of derivatives of the phosphonitrilic compounds can be prepared by means of the reactions at the P-Cl bonds. Hydrolysis reactions produce P-OH bonds that can then undergo esterification reactions. Substitution reactions that replace two chlorine atoms can occur at the same phosphoms atom (giving a geminal product) or on different phosphorus atoms. In the latter case, the two substituents can be on the same side of the ring in cis positions or on opposite sides of the ring in trans positions ... 

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