Nucleophilicity basicity

With the exception of the nuclear amination of 4-methylthiazole by sodium amide (341, 346) the main reactions of nucleophiles with thiazole and its simple alkyl or aryl derivatives involve the abstraction of a ring or substituent proton by a strongly basic nucleophile followed by the addition of an electrophile to the intermediate. Nucleophilic substitution of halogens is discussed in Chapter V. 

Taking into account the previous discussion of the reactivities of simple halogenothiazoles or nitrothiazoles, the mechanism of nucleophilic reac tivity of 2-halogeno-5-nitrothiazoles with an excess of basic nucleophile such as CHjO can be proposed (Scheme 14). 

The carbon-nitrogen triple bond of nitriles is much less reactive toward nucleophilic addition than is the carbon-oxygen double bond of aldehydes and ketones Strongly basic nucleophiles such as Gngnard reagents however do react with nitriles in a reaction that IS of synthetic value... 

Sinulatly, nucleophilic reagents are suitable for addition reactions only if they are not so strongly basic as to produce the cyanamide anion in large amounts. In such cases, dicyandiamide is produced or a cyanamide salt is obtained. Ai,Ai-Disubstituted cyanamides do not ionize, of course, and react easily with strongly basic nucleophiles. 

Reactions with strongly basic nucleophiles such as potassium amide in liquid ammonia may prove much more complex than direct substitution. 2-Chloro-4,6,7-triphenylpteridine reacts under these conditions via an S ANRORC mechanism to form 2-amino-4,6,7-triphenylpteridine and the dechlorinated analogue (78TL2021). The attack of the nucleophile exclusively at C-4 is thereby in good accord with the general observation that the presence of a chloro substituent on a carbon position adjacent to a ring nitrogen activates the position meta to the chlorine atom for amide attack. 

Chlorophthalazine is quite reactive to many basic nucleophiles but reacts sluggishly with aqueous or alcoholic alkali. In contrast, it is very rapidly hydrolyzed by warm, concentrated hydrochloric acid as are its diazine isomers. In hydrolysis with very dilute acid or with water, it forms some phthalazinone but mostly the self-con-densation product which hydrolyses to give 2-(l -phthalazinyl)-phthalazin-l-one (70% yield). Such self-condensations in diazanaph-thalenes and in monocyclic azines are always acid-catalyzed (Sections II, C and III,B). With methanolic methoxide, 1-chlorophthalazine (65°, few mins), its 7-methoxy analog (20°), and 1,6- and 1,7-dichlorophthalazines (20°) readily undergo mono-substitution. 

El eliminations begin with the same uni molecular dissociation we saw in the Sfsjl reaction, but the dissociation is followed by loss of H+ from the adjacent carbon rather than by substitution. In fact, the El and SN1 reactions normally occur together whenever an alkyl halide is treated in a protic solvent with a non-basic nucleophile. Thus, the best El substrates are also the best SN1 substrates, and mixtures of substitution and elimination products are usually obtained. For example, when 2-chloro-2-methylpropane is warmed to 65 °C in 80% aqueous ethanol, a 64 36 mixture of 2-methyl-2-propanol (Sjql) and 2-methylpropene (El) results. 

Secondary alkyl halides Sjvj2 substitution occurs if a weakly basic nucleophile is used in a polar aprotic solvent, E2 elimination predominates if a strong base is used, and ElcB elimination takes place if the leaving group is two carbons away from a carbonyl group. Secondary allylic and benzyiic alkyl halides can also undergo S l and El reactions if a weakly basic nucleophile is used in a pro tic solvent. 

Thus, like a, /1-unsaturated ketones and sulfones, both thiirene dioxides and thiirene oxides are preferentially attacked by the less basic nucleophiles on the vinylic carbon atom2. This would lead to formally 1,4 Michael-type adducts and/or other products resulting from further transformations following the initial formation of the a-sulfonyl and a-sulfoxy carbanions. 

Such weakly basic nucleophiles as (CNljC" or (N02)3C will not react with CS (28). Jensen and Hendriksen reported syntheses, reactions, and IR, NMR, and electronic spectra of 1,1-ethendithiols and their derivatives (29). 

To summarize in contrast to the observed nucleophilic attack of strongly basic nucleophiles on the sulfonyl and sulfoxy sulfur of the three-membered ring sulfones and sulfoxides, the acyclic sulfone and sulfoxide groups are attacked by nucleophiles only with difficulty Although the precise reason for this difference is as yet not clear, it is most probably associated with the geometry, electronic structure, bonding and strain energy of the cyclic compounds. 

The behavior of the different amines depends on at least four factors basicity, nucleophilicity, steric hindrance and solvation. In the literature (16), 126 aliphatic and aromatic amines have been classified by a statistical analysis of the data for the following parameters molar mass (mm), refractive index (nD), density (d), boiling point (bp), molar volume, and pKa. On such a premise, a Cartesian co-ordinate graph places the amines in four quadrants (16). In our preliminary tests, amines representative of each quadrant have been investigated, and chosen by consideration of their toxicity, commercial availability and price (Table 1). 

General-base catalysis can, as the name suggests, be accomplished by any adequately strong base, whereas very special demands are placed upon compounds acting as nucleophilic catalysts. The efficiency of these catalysts depends on three factors basicity, nucleophilicity, and leaving-group ability [166], Each of these characteristics is in turn the combined result of several attributes. 

The basicity, nucleophilicity, polarizability and steric requirements of the nucleophile have been recently shown to affect the SjyAr reactions with amines. 

The authors have also studied the deprotection by less basic nucleophiles such as thiophenolate and iodide. Deprotection by the latter anion may lead to a side-reaction when condensation of the allyl iodide formed with the de-protected phosphorothioate leads to the corresponding S-allyl phosphoroth-ioate. To suppress this side reaction thiourea was used to trap the allyl iodide. 

In addition, acid cocatalysts can assist the formation of the enamine. With very basic, nucleophilic amines, such as pyrrolidine and its derivatives, acid catalysis is not necessarily required for enamine formation. However, with less basic amines, Brpnsted or Lewis acids are often used to assist in enamine formation (Scheme 7). 

In light of these significant challenges, Evans and Leahy reexamined the rhodium-catalyzed allylic alkylation using copper(I) enolates, which should be softer and less basic nucleophiles [23]. The copper(I) enolates were expected to circumvent the problems typically associated with enolate nucleophiles in metal-allyl chemistry, namely ehmina-tion of the metal-aUyl intermediate and polyalkylation as well as poor regio- and stereocontrol. Hence, the transmetallation of the lithium enolate derived from acetophenone with a copper(I) hahde salt affords the requisite copper] I) enolate, which permits the efficient regio- and enantiospecific rhodium-catalyzed allylic alkylation reaction of a variety of unsymmetrical acychc alcohol derivatives (Tab. 10.3). 

A variety of basic (nucleophilic) initiators have been used to initiate anionic polymerization [Bywater, 1975, 1976, 1985 Fontanille, 1989 Hsieh and Quirk, 1996 Morton, 1983 Morton and Fetters, 1977 Quirk, 1995, 1998, 2002 Richards, 1979 Szwarc, 1983 Young et al., 1984]. These include covalent or ionic metal amides such as NaNFU and LiN(C2H5)2, alkoxides, hydroxides, cyanides, phosphines, amines, and organometallic compounds such as n-C4H9Li and <)>MgBr. Initiation involves the addition to monomer of a nucleophile (base), either a neutral (B ) or negative (B ) species. 

Baylis-Hillman reactions, the protonated amine was the governing factor in determining catalyst efficiency, thus making quinuclidine itself a better catalyst than 3-heteroatom substituted analogs, which are of reduced basicity/nucleophilic-ity and consequently give lower reaction rates. 

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