Nucleophilic reactions reactivity

Nonanedione, another 1,3-difunctional target molecule, may be obtained from the reaction of hexanoyl chloride with acetonide anion (disconnection 1). The 2,4-dioxo substitution pattern, however, is already present in inexpensive, symmetrical acetylacetone (2,4-pentanedione). Disconnection 2 would therefore offer a tempting alternative. A problem arises because of the acidity of protons at C-3 of acetylacetone. This, however, would probably not be a serious obstacle if one produces the dianion with strong base, since the strongly basic terminal carbanion would be a much more reactive nucleophile than the central one (K.G. Hampton, 1973 see p. 9f.). 

Alkylation can also be accomplished with electrophilic alkenes. There is a dichotomy between basic and acidic conditions. Under basic conditions, where the indole anion is the reactive nucleophile, A-alkylation occurs. Under acidic conditions C-alkylation is observed. The reaction of indole with 4-vinylpyri-dine is an interesting illustration. Good yields of the 3-alkylation product are obtained in refluxing acetic acid[18] whereas if the reaction is done in ethanol containing sodium ethoxide 1-alkylation occurs[19]. Table 11.2 gives some examples of 3-alkylation using electrophilic alkenes. 

The principal reactions of this class of compounds are summarized in Scheme 172. In most of these reactions the reactive nucleophilic center is the terminal NHj group, although the other exocyclic nitrogen may also be involved, as shown by acetylation, which yields 284 and 285. However, the structure of compound 281 is not the one proposed in a recent report (1582) that attributes the attack to the other exocyclic nitrogen. The formation of osazones (287) from sugars, 2-hydrazinothiazoles, and hydrazine has been reported (525, 531). 

Thermodynamic properties such as heats of reaction and heats of formation can be computed mote rehably by ab initio theory than by semiempirical MO methods (55). However, the Hterature of the method appropriate to the study should be carefully checked before a technique is selected. Finally, the role of computer graphics in evaluating quantum mechanical properties should not be overlooked. As seen in Figures 2—6, significant information can be conveyed with stick models or various surfaces with charge properties mapped onto them. Additionally, information about orbitals, such as the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO), which ate important sites of reactivity in electrophilic and nucleophilic reactions, can be plotted readily. Figure 7 shows representations of the HOMO and LUMO, respectively, for the antiulcer dmg Zantac. 

The very high reactivity of the P—Cl bonds in (4) forms the basis for the now well-known macromolecular substitution method, which has been used to synthesize polymers of types (1) and (2) and some polymers that are hybrids of these and (3). The method involves nucleophilic reactions of (4), and to some extent of its difluoro analogue, with alkoxides or amines. 

Chapters 1 and 2. Most C—H bonds are very weakly acidic and have no tendency to ionize spontaneously to form carbanions. Reactions that involve carbanion intermediates are therefore usually carried out in the presence of a base which can generate the reactive carbanion intermediate. Base-catalyzed condensation reactions of carbonyl compounds provide many examples of this type of reaction. The reaction between acetophenone and benzaldehyde, which was considered in Section 4.2, for example, requires a basic catalyst to proceed, and the kinetics of the reaction show that the rate is proportional to the catalyst concentration. This is because the neutral acetophenone molecule is not nucleophihc and does not react with benzaldehyde. The much more nucleophilic enolate (carbanion) formed by deprotonation is the reactive nucleophile. 

For general reviews of nucleophilicity, see R. F. Hudson, in Chemical Reactivity and Reaction Paths, G. Klopman, ed., John Wiley Sons, New York, 1974, Chapter 5 J. M. Harris and S. P. McManus, eds., Nucleophilicity, Advances in Chemistry Series, fio. 215, American Chemical Society, lA asbingtuo, D.C., 1987. 

Frontier Orbitals and Chemical Reactivity. Chemical reactions typically involve movement of electrons from an electron donor (base, nucleophile, reducing agent) to an electron acceptor (acid, electrophile, oxidizing agent). This electron movement between molecules can also be thought of as electron movement between molecular orbitals, and the properties of these electron donor and electron acceptor orbitals provide considerable insight into chemical reactivity. 

A few studies on solvolyses by alcohols and by water are available. The hydrolyses studied include displacement of alkylamino groups from acridine antimalarials and of halogen from other systems. In all cases, these reactions appeared to be first-order in the heterocyclic substrate. By a detailed examination of the acid hydrolysis of 2-halogeno-5-nitropyridine, Reinheimer et al. have shown that the reaction rate varies as the fourth power of the activity of water, providing direct evidence that the only reactive nucleophile is neutral water, as expected. 

Various nucleophilic reactions of polysubstituted 5-halopyri-midines are described in Section II,E,2,e with postulates to explain the degree of reactivity. For pyrimidine derivatives, the effect of the following on nucleophilic substitution is included in earlier sections hydrogen bonding and cationization in Section II, C, the leaving group in Section II, D, and the nucleophile in Sections II,E,2,e and II, F. 

Nucleophilic aromatic substitution of hydrogen in heteroaromatic compounds, reactivity and reaction mechanisms 94MI2. 

The aldol reaction is catalyzed by acid as well as by base. What is the reactive nucleophile in the acid-catalyzed aldoJ reaction Propose a mechanism. 

NMR chemical shift data from die protons ortho or para to the electron-withdrawing group can be used to determine the reactivity of the monomer indirecdy.58 Carbon-13 and 19F NMR can be used to probe the chemical shift at the actual site of nucleophilic reaction. In general, lower chemical shifts correlate widi lower monomer reactivity. Carter reported that a compound might be appropriate for nucleophilic displacement if the 13 C chemical shift of an activated Buoride ranges from 164.5 to 166.2 ppm in CDC1359. 

For a monograph, see Harris, J.M. McManus, S.P. Nucleophilicity American Chemical Society Washington, 1987. For reviews, see Klumpp, G.W. Reactivity in Organic Chemistry Wiley NY, 1982, pp. 145, 181 Hudson, R.F. in Klopman Chemical Reactivity and Reaction Paths Wiley NY, 1974, p. 167. 

Especially for large-scale work, esters may be more safely and efficiently prepared by reaction of carboxylate salts with alkyl halides or tosylates. Carboxylate anions are not very reactive nucleophiles so the best results are obtained in polar aprotic solvents45 or with crown ether catalysts.46 The reactivity order for carboxylate salts is Na+ < K+ < Rb+ < Cs+. Cesium carboxylates are especially useful in polar aprotic solvents. The enhanced reactivity of the cesium salts is due to both high solubility and minimal ion pairing with the anion 47 Acetone is a good solvent for reaction of carboxylate anions with alkyl iodides48 Cesium fluoride in DMF is another useful... 

Given their extraordinary reactivity, one might assume that o-QMs offer plentiful applications as electrophiles in synthetic chemistry. However, unlike their more stable /tora-quinone methide (p-QM) cousin, the potential of o-QMs remains largely untapped. The reason resides with the propensity of these species to participate in undesired addition of the closest available nucleophile, which can be solvent or the o-QM itself. Methods for o-QM generation have therefore required a combination of low concentrations and high temperatures to mitigate and reverse undesired pathways and enable the redistribution into thermodynamically preferred and desired products. Hence, the principal uses for o-QMs have been as electrophilic heterodienes either in intramolecular cycloaddition reactions with nucleophilic alkenes under thermodynamic control or in intermolecular reactions under thermodynamic control where a large excess of a reactive nucleophile thwarts unwanted side reactions by its sheer vast presence. 

Irreversible inhibition is probably due to the alkylation of a histidine residue.43 Chymotrypsin is selectively inactivated with no or poor inhibition of human leukocyte elastase (HLE) with a major difference the inactivation of HLE is transient.42,43 The calculated intrinsic reactivity of the coumarin derivatives, using a model of a nucleophilic reaction between the ligand and the methanol-water pair, indicates that the inhibitor potency cannot be explained solely by differences in the reactivity of the lactonic carbonyl group toward the nucleophilic attack 43 Studies on pyridyl esters of 6-(chloromethyl)-2-oxo-2//-1 -benzopyran-3-carboxylic acid (5 and 6, Fig. 11.5) and related structures having various substituents at the 6-position (7, Fig. 11.5) revealed that compounds 5 and 6 are powerful inhibitors of human leukocyte elastase and a-chymotrypsin thrombin is inhibited in some cases whereas trypsin is not inhibited.21... 

Two alternatives to conventional acid/base hydrolyses for cleaving esters are Sn2 displacement of the carboxylate group by reactive nucleophiles and nucleophilic attack at the carbonyl carbon. In this latter context we investigated the reaction of S-b-MM with potassium trimethylsilanolate, a so-called potassium superoxide equivalent (15). One advantage that this reagent has over potassium... 

The compounds referred to as azolides are heterocyclic amides in which the amide nitrogen is part of an azole ring, such as imidazole, pyrazole, triazole, tetrazole, benzimidazole, benzotriazole, and their substituted derivatives. In contrast to normal amides, most of which show particularly low reactivities in such nucleophilic reactions as hydrolysis, alcoholysis, aminolysis, etc., the azolides are characterized by high reactivities in reactions with nucleophiles within the carbonyl group placing these compounds at about the same reactivity level as the corresponding acid chlorides or anhydrides. 11... 

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