Reactivity with the Attacking Nucleophile

The second variable is the nature of the attacking nucleophile and we shall consider first the reactivities of a series of nucleophiles towards a single substrate. Perhaps the most studied compound is 1,3,5-trinitro-benzene and the equilibrium constants for formation of 1 1 adducts with a variety of nucleophiles are given in Table 7. However the stability of a given adduct will vary considerably with change of solvent so that values obtained in different solvents are not comparable. 

In fact these equilibrium constants give a measure of the thermo- 

Equilibrium Constants for Formation of Adducts from 1,3,5-Trinitrobenzene with Various Nucleophiles 

With 1,3,5-trinitrobenzene no diversity of attack is possible, though for substituted derivatives such as 2,4,6-trinitroanisole or 2,4,6-trinitro-aniline the mode of interaction may vary on changing the nucleophile. Thus structural measurements show that the thermodynamically stable adducts of 2,4,6-trinitroanisole with OMe-, Ns- or NEt2 result from addition at Cl while the apparently stable adducts with S03 or CHg CO CH2 are formed at C3. The failure to detect addition of these latter nucleophiles at Cl may be ascribed to steric strain. This may occur either in the Cl adducts themselves, so that they are no longer thermodynamically preferred to the C3 adducts, or alternatively in the transition states for their formation, so that their formation is very slow. Again the mode of ionization of 2,4,6-trinitroaniline and its N-substituted derivatives depends on the relative affinities for carbon or hydrogen of the particular nucleophile used. Thus sulphur bases such as SEt- and SPh will preferentially add at the 3-position, while with oxygen bases abstraction of an amino proton also occurs. 

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The exchange reaction of 1-bromonaphthalene with CuCl proceeds effectively in polar solvents, such as DMF or DMSO, at temperatures of 110-150 °C via a second-order mechanism. The reaction is reversible but the equilibrium favors formation of aryl chlorides. The catalysis is inhibited by chloride anion and by pyridine or, particularly, 2,2 -bipyri-dine. The ease of replacement decreased in the order Arl> ArBr> ArCl and the reactivity of the attacking nucleophile decreased in the order CuCl> CuBr> Cul. The exchange reac-... 

Ionisation of the hydroxy groups in cellulose is essential for the nucleophilic substitution reaction to take place. At neutral pH virtually no nucleophilic ionised groups are present and dye-fibre reaction does not occur. When satisfactory exhaustion of the reactive dye has taken place, alkali is added to raise the pH to 10-11, causing adequate ionisation of the cellulose hydroxy groups. The attacking nucleophile ( X ) can be either a cellulosate anion or a hydroxide ion (Scheme 7.8), the former resulting in fixation to the fibre and the latter in hydrolysis of the reactive dye. The fact that the cellulosic substrate competes effectively with water for the reactive dye can be attributed to three features of the reactive dye/ cellulosic fibre system ... 

As can be seen from Table 2 rates of reaction of nucleophiles with phenyl benzenethiolsulfinate vary markedly with nucleophile structure (Kice and Liu, 1979). The particular reactivity pattern observed will be discussed later in Section 8 in conjunction with data on the reactivity of the same nucleophiles toward phenyl benzenethiolsulfonate, PhS02SPh. Of significance at present is the fact that PhS is much more reactive than nucleophiles such as OH- or CH30. In the alkaline hydrolysis of PhS(0)SPh (Oae et al., 1977b Kice and Rogers, 1974a) this means that the thiophenoxide liberated by the initial attack of OH- on PhS(0)SPh (28) will rapidly react with a second molecule of thiolsulfinate to form disulfide and sulfenate ion (29). 

It is generally agreed that propagation in the cationic polymerization of cyclic ethers occurs after nucleophilic attack by the monomer oxygen atom (equation 3). Therefore, many authors attempt to explain their copolymerization data by noting that the more basic monomer has the higher reactivity with the active chain end. The order of basicity which has been established (36, 38) is ... 

The reason for the lack of SN2 reactivity in ethenyl or ethynyl halides may be that the attacking nucleophile is unable to react by the concerted inversion mechanism that invariably is observed with alkyl halides ... 

In the first step ester 50 is formed from secondary alcohol 15 and acid 16 Dicyclohexylcarbodiimide (51) activates acid 16 for attack by the nucleophile. First the acid is deprotonated and then the resulting carixjxylate 52 adds to the prolonaled cart xliimide species 53, leading to an O-acylisourea, 54. This actuated ester is very reactive with respect to nucleophiles, and as a result of attack by alcohol 15 the urea derivative 55 is eliminated producing the desired ester 50. 

The khietics of die reactions of 1 -halo-2.4-dinitrobcnzcncs with aliphatic amines have been used to probe solvent effects in mixtures of chloroform or dichloromethane with polar hydrogen-bond acceptors, such as DMSO. In these reactions, nucleophilic attack is rate limiting. Attempts to correlate reactivity with the empirical solvent... 

Reactions of carbocations with free CN- occur preferentially at carbon, and not nitrogen as predicted by the principle of hard and soft acids and bases.69 Isocyano compounds (N-attack) are only formed with highly reactive carbocations where the reaction with cyanide occurs without an activation barrier because the diffusion limit has been reached. A study with the nitrite nucleophile led to a similar observation.70 This led to a conclusion that the ambident reactivity of nitrite in terms of charge control versus orbital control needs revision. In particular, it is proposed that SNl-type reactions of carbocations with nitrite only give kinetically controlled products when these reactions proceed without activation energy (i.e. are diffusion controlled). Activation controlled combinations are reversible and result in the thermodynamically more stable product. The kinetics of the reactions of benzhydrylium ions with alkoxides dissolved in the corresponding alcohols were determined.71 The order of nucleophilicities (OH- MeO- < EtO- < n-PrCT < / -PrO ) shows that alkoxides differ in reactivity only moderately, but are considerably more nucleophilic than hydroxide. 

The delocalizability descriptors characterizing molecular reactivities toward the attack of a nucleophile (DN cf. Table 6.1 and Equation 6.58) and electrophile (DE cf. Table 6.1 and Equation 6.59) have been calculated and analyzed comparatively only for the three semiempirical methods AMI, PM3, and PM5. The resultant statistics are summarized in Table 6.9 and show generally high intercorrelations, but also some cases with only moderate to low R2 values. 

Under these conditions, the order of reactivity to nucleophilic substitution changes dramatically from that observed in the Sn2 reaction, such that tertiary alkyl halides are more reactive then secondary alkyl halides, with primary alkyl halides not reacting at all. Thus a different mechanism must be involved. For example, consider the reaction of 2-iodo-2-methylpropane with water. (Following fig.). In it, the rate of reaction depends on the concentration of the alkyl halide alone and the concentration of the attacking nucleophile has no effect. Thus, the nucleophile must present if the reaction is to occur, but it does not matter whether there is one equivalent of the nucleophile or an excess. Since the reaction rate depends only on the alkyl halide, the mechanism is called the SN1 reaction, where SN stands for substitution nucleophilic and the 1 shows that the reaction is first order or unimolecular, i.e. only one of the reactants affects the reaction rate. 

Steric factors also play an important role in the reactivity of aldehydes and ketones. We may look at the relative ease with which the attacking nucleophile can approach the carbonyl carbon or consider how steric factors influence the stability of the transition state leading to the final product. 

Here follows a list of carbonyl substituents that prevent enolization. They are arranged roughly in order of reactivity with the most reactive towards nucleophilic attack by an enolate at the top. You do, of course, need two substituents to block enolization so typical compounds also appear in the list. 

Spiroacylal 2 was designed under the rationale that the constraint of the carbonyl groups into a conformation in which overlap of their 7r-orbitals with the bent bonds of the cyclopropane is assured should dramatically increase the vulnerability of the cyclopropane toward nucleophilic attack.8 Experimental support for this notion is abundant.8 Spiroacylal 2 is considerably more reactive than 1,1-dicarbethoxycyclopropane in such reactions. For instance, reaction of 2 with piperidine occurs at room temperature. The corresponding reaction in the case of the diester is conducted at 110°C.5 Reactions with enolates also occur under mild conditions.8 Compound 2 reacts with the weak nucleophile pyridine at room temperature to give a betaine.8 An illustrative mechanism for the reaction of the acylal 2 with aniline to afford 2-oxo-l-phenyl-3-pyrrolidinecarboxylic acid (3) is... 

In a series of theoretical calculations of addition to protonated formaldehyde it was also revealed that the intrinsic properties of the attacking nucleophile (X) are reflected in the bond energy of the X-CH2-OH+ intermediate (X = NH3 >H20 >HF >H2), and in the barrier for the subsequent 1,3-intramolecular proton transfer leading to water elimination [129]. In comparing different substituents X and Y, it was also found that for the same X,but different CH2Y+ ions the reactivity order is Y = NH2 reactions with formamide, it has been found that Y = OH [Pg.16]

Abstract The chapter reviews the classic Reissert reaction, the keystone of a broad family of multicomponent reactions involving azines, electrophilic reagents and nucleophiles to yield A,a-disubstituted dihydroazine adducts. The first sections deal with the standard nucleophilic attack upon activated azines, including asymmetric transformations. Section 5 focuses on the generation of dipolar intermediates by azine activation, and on their subsequent transformation chiefly in cycloadditions. Lastly, Sect. 6 is primarily devoted to a special branch of this chemistry involving isocyanides. It also covers the reactivity of dihydroazines and reviews the mechanistic proposals for related reactions. 

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