Nucleophilic aliphatic structural effects

HARTSHORN, s. R. Aliphatic Nucleophilic Substitution (CUP, 1973). HiNE, j. Structural Effects on Equilibria in Organic Chemistry (Wiley, 1975). 

The polymers used in this study were prepared by a nucleophilic activated aromatic substitution reaction of a bisphenate and dihalo diphenyl sulfone ( ). The reaction was carried out in an aprotic dipolar solvent (NMP) at 170°C in the presence of potassium carbonate (Scheme 1) (5,6). The polymers were purified by repeated precipitation into methanol/water, followed by drying to constant weight. The bisphenols used were bisphenol-A (Bis-A), hydroquinone (Hq) and biphenol (Bp). Thus, the aliphatic character of Bis-A could be removed while retaining a similar aromatic content and structure. The use of biphenol allows an investigation of the possible effect of extended conjugation on the radiation degradation. 

An obvious difficulty arises with this rather elaborate rationale when phosphoramidate and aryl phosphoramidate monoanions are compared for example, the dissimilarity of the dioxan effect yet the identity of product distribution observed in methanol-water competition experiments. Preliminary studies in the author s laboratory have revealed striking differences in the hydrolytic behavior between a series of phosphoramidafes derived from primary aliphatic amines and the above aryl systems. No linear structure-reactivity relationship between the logarithmic rate of hydrolysis of the monoanion species and the pKa of the amine is observed19. Moreover, the rate of hydrolysis of phosphoramidate monoanions derived from aliphatic amines is at least 104 times slower than those formed from aryl amines. In contrast, only a thirtyfold decrease in rate is observed for the corresponding ApKa in the O-phos-phate monoester series. The suspicion that mechanism (1), even with the above proposed modification, is not an accurate description of phosphoramidate monoanion hydrolysis derives some further support from the observation that the monoanion is subject to nucleophilic attack by substituted pyridines al-... 

The reaction of sulphides with (dichloroiodo)benzene can lead to several kinds of products depending on the substrate and the reaction conditions [19]. Sulphides of great structural diversity (aliphatic, aromatic, heterocyclic) were oxidized efficiently by (dichloroiodo)benzene (one equivalent) in aqueous pyridine. The reaction was almost instantaneous and not noticeably sensitive to steric or electronic effects. Ethylenic double bonds were not attacked under these conditions however, in vinylic sulphides containing an electron-withdrawing group (COOH or RSO) ft- to the sulphur atom the oxidation was accompanied by nucleophilic attack to the double bond resulting in a mixture of products. The method is suitable for the preparation of I80-labelled sulphoxides using small quantities of H2,80. 

Studies on thiamine (vitamin Bi) catalyzed formation of acyloins from aliphatic aldehydes and on thiamine or thiamine diphosphate catalyzed decarboxylation of pyruvate have established the mechanism for the catalytic activity of 1,3-thiazolium salts in carbonyl condensation reactions. In the presence of bases, quaternary thiazolium salts are transformed into the ylide structure (2), the ylide being able to exert a cat ytic effect resembling that of the cyanide ion in the benzoin condensation (Scheme 2). Like cyanide, the zwitterion (2), formed by the reaction of thiazolium salts with base, is nucleophilic and reacts at the carbonyl group of aldehy s. The resultant intermediate can undergo base-catalyzed proton... 

Competitive effects for the interactions of cisplatin with various active sites in the cellular environment are discussed in papers of Deubel.55,56 In the earlier paper, energetic and structural data of complexes with the different substituted ligands were explored. The more recent work deals with kinetic factors in the relation to the transition state (TS) for water replacement of the semihydrated cisplatin complex (cis-[Pt(NH3)2(H20)Cl]+ ) with either an N- or S-containing ligand (thiopheneimidazol, dimethyl sulphide, or methanethiolate which serve as amino acid models). Deubel concluded the kinetic preference of N-sites over S-nucleophiles where the important role is played by the electrostatic terms. In addition, the aliphatic/aromatic character of the substituent as well as the influence of different dielectric constants of the environment are very important. A more realistic model for the aqua-ligand replacement with adenine and guanine was studied in works of Chval et al.53,57 and Eriksson and coworkers.58 They performed independently the estimation of the thermodynamic and kinetic parameters of this process. 

If equimolar quantities of tetramethylammonium fluoride and a threefold excess of Me3SiCF3 or its homologues are used the perfluoroalkyltrimethyl silane acts as an effective source of nucleophilic perfluoroalkyl equivalents for nucleophilic substitution of aliphatic triflates [90] (Scheme 2.136). This method enables the simple synthesis of partially fluorinated alkane structures which are of interest in the chemistry of liquid crystals and other functional materials. 

It is also important to recognise that the structure of the amine nucleophile will have a major effect on the reactivity of the system. Thus aromatic amines such as 4,4 -diamino-diphenyl sulfone (DDS), shown in Scheme 1.6, will be much weaker bases and less reactive than aliphatic amines, so high temperatures are required for reachon to occur in the absence of added catalysts. 

The measured half-lives range from 19 sec to 7000 yr, suggesting that structure variation can have significant effects on hydrolysis rates. The reactivity of these chemicals can be rationalized in terms of the limiting mechanisms presented for nucleophilic substitution. It is apparent from the data in Table 2.2 that the fluori-nated aliphatics are much more stable than the chlorinated aliphatics, which in turn are more stable than the brominated aliphatics. This trend in reactivity reflects the strength of the carbon-halogen bond, which follows the order F>Cl>Br, that is broken in the nucleophilic substitution reaction. 

The solvolysis reactions of cyclopropylmethyl systems also provide evidence for the intermediacy of carbonium ions in nucleophilic substitution reactions. We have seen in Table 5.2 that the stabilizing effect a cyclopropyl group exerts on a carbonium ion is appreciable. A similar effect is evident on comparing rates of hydrolysis of cyclopropylmethyl compounds with model aliphatic compounds. The tertiary p-nitrobenzoates represented by the structure 1 had the relative rates indicated for hydrolysis in 80% aqueous dioxane at 60°C ... 

---