Nucleophile with conjugate acid

The formation of the above anions ("enolate type) depend on equilibria between the carbon compounds, the base, and the solvent. To ensure a substantial concentration of the anionic synthons in solution the pA" of both the conjugated acid of the base and of the solvent must be higher than the pAT -value of the carbon compound. Alkali hydroxides in water (p/T, 16), alkoxides in the corresponding alcohols (pAT, 20), sodium amide in liquid ammonia (pATj 35), dimsyl sodium in dimethyl sulfoxide (pAT, = 35), sodium hydride, lithium amides, or lithium alkyls in ether or hydrocarbon solvents (pAT, > 40) are common combinations used in synthesis. Sometimes the bases (e.g. methoxides, amides, lithium alkyls) react as nucleophiles, in other words they do not abstract a proton, but their anion undergoes addition and substitution reactions with the carbon compound. If such is the case, sterically hindered bases are employed. A few examples are given below (H.O. House, 1972 I. Kuwajima, 1976). 

The achiral triene chain of (a//-rrans-)-3-demethyl-famesic ester as well as its (6-cis-)-isoiner cyclize in the presence of acids to give the decalol derivative with four chirai centres whose relative configuration is well defined (P.A. Stadler, 1957 A. Escherunoser, 1959 W.S. Johnson, 1968, 1976). A monocyclic diene is formed as an intermediate (G. Stork, 1955). With more complicated 1,5-polyenes, such as squalene, oily mixtures of various cycliz-ation products are obtained. The 18,19-glycol of squalene 2,3-oxide, however, cyclized in modest yield with picric acid catalysis to give a complex tetracyclic natural product with nine chiral centres. Picric acid acts as a protic acid of medium strength whose conjugated base is non-nucleophilic. Such acids activate oxygen functions selectively (K.B. Sharpless, 1970). 

The reaction of alkenyl mercurials with alkenes forms 7r-allylpalladium intermediates by the rearrangement of Pd via the elimination of H—Pd—Cl and its reverse readdition. Further transformations such as trapping with nucleophiles or elimination form conjugated dienes[379]. The 7r-allylpalladium intermediate 418 formed from 3-butenoic acid reacts intramolecularly with carboxylic acid to yield the 7-vinyl-7-laCtone 4I9[380], The /i,7-titisaturated amide 421 is obtained by the reaction of 4-vinyl-2-azetidinone (420) with an organomercur-ial. Similarly homoallylic alcohols are obtained from vinylic oxetanes[381]. 

Alkylation of 2-methylaminothiazole (204) with ROH in 85% sulfuric acid gives 2-methylimino-3-alkyl-4-thiazoIine (54). 2-Amino-4-rnethyl-thiazoie alkylated with an excess of isopropanol, however, gives 95% of 2-isopropylamino-4-methyl-5-isopropylthiazole (56). The same result is obtained with cyclohexanol (242). These results and those reported in Sections III.l.C and IV.l.E offer interesting new synthetic possibilities in thiazole chemistry. The reactive species in these alkylations is the conjugate acid of 2-aminothiazole. and the diversity of the products obtained suggests that three nucleophilic centers may be operative in this species. 

We can extend the general principles of electrophilic addition to acid catalyzed hydration In the first step of the mechanism shown m Figure 6 9 proton transfer to 2 methylpropene forms tert butyl cation This is followed m step 2 by reaction of the car bocation with a molecule of water acting as a nucleophile The aUcyloxomum ion formed m this step is simply the conjugate acid of tert butyl alcohol Deprotonation of the alkyl oxonium ion m step 3 yields the alcohol and regenerates the acid catalyst... 

The most common manifestation of a structure-reactivity correlation in a reaction series of this type is a plot of log k for the reaction against pX of the conjugate acid of the nucleophile. Of course, this is identical with the graphical presentation... 

A nucleophile with a negative charge is always a more powerful nucleophile than its conjugate acid (assuming the latter is also a nucleophile). Thus OH is more powerful than H2O, NH2 is more powerful than NH3, and so on. 

Solid-liquid PTC conditions in which the nucleophilic salts (organic or mineral) are transferred from the solid state (as they are insoluble) to the organic phase by means of a phase-transfer agent. Most often the organic nucleophilic species can be formed by reaction of their conjugated acids with solid bases (sodium or potassium hydroxides, or potassium carbonate) (Scheme 5.1 path b). Another proposed mechanism suggests that interfacial reactions occur as a result of absorption of the liquid phase on the surface of the solid. 

The effect is interpreted as evidence of the operation of the homo-/hetero-conjugate mechanism. The authors presume that for the mechanism given by equation 1, for additives P which are much less basic than the nucleophile N, electrophilic catalysis also occurs both with the hetero-conjugate N+HP formed between the conjugate acid of the nucleophile, N, and P, as well as with the homo-conjugate Nu+HNu. For more basic additives, electrophilic catalysis is possible by the species PH+ and its homo-conjugate PHP+153 162 182. 

The interpretation of formation of homo- (or hetero-) conjugated acid BH+B by proton transfer from the intermediate and the electrophilically catalysed departure of the nucle-ofuge due to this aggregate is common to this and to the dimer mechanism and they can be formulated as essentially the same, and as reflecting different parts of a spectrum of methods for the formation of the second intermediate153. For a given nucleophile, dimer formation increases with increase of concentration, hence the relative importance that reaction via a dimer should increase with increasing nucleophile concentration. 

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