Halo group, directing effect

Hagemann s ester, synthesis of, 912 Halo group, directing effect of, 567-568... 

Substitution reactions by the ionization mechanism proceed very slowly on a-halo derivatives of ketones, aldehydes, acids, esters, nitriles, and related compounds. As discussed on p. 284, such substituents destabilize a carbocation intermediate. Substitution by the direct displacement mechanism, however, proceed especially readily in these systems. Table S.IS indicates some representative relative rate accelerations. Steric effects be responsible for part of the observed acceleration, since an sfp- caibon, such as in a carbonyl group, will provide less steric resistance to tiie incoming nucleophile than an alkyl group. The major effect is believed to be electronic. The adjacent n-LUMO of the carbonyl group can interact with the electnai density that is built up at the pentacoordinate carbon. This can be described in resonance terminology as a contribution flom an enolate-like stmeture to tiie transition state. In MO terminology,.the low-lying LUMO has a... 

Hydroxyl groups can be introduced by hydrolytic reactions in the electrophilic 2-, 4-and 6-positions, and direct hydrolysis of halopyrimidines can be effected under both acidic and alkaline conditions <1994HC(52)1>. Normally 4-halopyrimidines hydrolyze faster than 2-halo derivatives, but in the case of 2-chloro, 6-di(pyrrolidinyl)pyrimidine 163 and 4-chloro-2,6-di(pyrrolidinyl)pyrimidine 164, the 2-chloro isomer 163 was found to hydrolyze 350 times faster (to 165) than the 6-chloro isomer 164 in 6N HCl, and 1750 times faster in 12N HCl <20060PD921>. This result was interpreted as being due to the transition state for hydrolysis of the 4-chloro isomer involving two more molecules of water (each acting as a base) than the transition state for hydrolysis of the 2-chloro isomer. As the concentration of HCl increases from 6 N to 12 N, there are fewer unprotonated water molecules and thus, hydrolysis of the 4-isomer is less favored. This difference in reactivity was able to be exploited to perform a selective hydrolysis on a production scale <20060PD921>. 

An interesting study reported in 2001, although it did not utilize any inverse-detected 2D NMR data, did report a wealth of useful chemical shift data for parent azoles and benzazoles. Solid-state chemical shift data were reported for several pyrazole analogues by Alvarez-Larena. Trofimenko et al reported a study of the buttressing effects of the A-tert-h xiy group of a series of pyrazoles in the solid state, followed by a study by Claramunt and co-workers of a series of halo triazoles. Martins and co-workers reported data for a series of 5-trichloromethyl-1,2-dimethyl-1/f-pyrazolium chlorides. Malpass and co-workers reported direct observe chemical shift data for a series of bicyclic amines and lactams. Recently, a large body of chemical shift data for a series of l,4-diazaspiro[4.5]decanes and l,4-oxazaspiro[4.5]-decanes using direct observe methods were reported by Ariza-Castolo and co-workers. " Readers with an interest in the chemical shift behavior of these systems are directed to these references as a source of data. 

Direct replacement of hydrogen by an amino group can be effected only in a few special cases but then has considerable preparative interest. Animating agents requiring consideration are alkali amides, hydroxylamine, and A-halo amines. 

---