The Attacking Nucleophile

The results in Table 6.2 suggest that no unique order of reactivity applying in all reactions can be given. However, an approximate order of decreasing reactivity [1,32] that applies to most situations is NHj RS AlkO PhO piperidine OH aniline ammonia halide ions water. 

There is some dependence on the basicity of the nucleophile, measured by the pK value of its corresponding acid particularly in series of structurally related nucleophiles. Examples are in the reactions of m- and p-substituted anilines with l-chloro-2,4-dinitrobenzene [1] and of substituted phenoxide ions with halogenonitrobenzenes [9]. Similarly, the reactivities of m- and p-substituted thiophenoxide ions with l-chloro-2,4-dinitrobenzene closely parallel their basicities [56]. 

The reduced reactivity here of o-methyl thiophenoxide may be ascribed to steric factors. In these and other examples, relatively good correlations with the Hammett and Brpnsted equations may be observed, and it has been noted [57] that when nucleophilic attack is rate limiting, the Brpnsted value is usually in the range 0.5-0.7. Studies of the substitution reactions of halogenonitrobenzenes with nucleophiles, including substituted fluorenide carbanions, such as (12), and phenothiazine nitranions (13) in DMSO solvent [53] indicated that for anions of the same basicity, the nucleophilic reactivity was in the order S C 0 N. The high reactivity of thianions is most likely due to their high polarizability. 

It should also be noted that there is the possibility of complications arising from reaction of the nucleophile with the solvent to give the lyate anions. For example, phenoxides may react with alcohols to form alkoxide ions, so that reaction of 4-nitrofluorobenzene with sodium phenoxide in methanol was found to give 99% of 4-nitroanisole and only 1 % of the nitrophenyl phenyl ether [58]. 

Attempts to obtain general measures of nucleophilic reactivity include that of Ritchie [59]. He initially measured rate constants for combination of anionic nucleophiles with organic cations, such as triarylmethyl and tropylium cations, and was able to obtain the relation given in Equation 6.1 for nucleophilicity. Here, k and q are respectively the rate constants for reaction of the cation with the nucleophile and with water. 

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Qualitative models of reactivity and quantum mechanical calculations of reaction paths both indicate an angular approach of the attacking nucleophile to the first-row sp -hybridized electrophilic centers M at intermediate and reactive distances, 29. The geometry of 29 is also characteristic for the case of nucleophilic addition to electron-deficient centers of main-group 12 and 13 elements. By contrast, a linear arrangement 30 of making and breaking bonds is required for sp -hybridized first-row centers (C, N, O)... 

The reaction is similar to the reduction of a nitrile to an amine, except that only one nucleophilic addition occurs rather than two, and the attacking nucleophile is a carbanion (R ) rather than a hydride ion. For example ... 

An opportunity to investigate the relative leaving ability of fluorine in the same molecule was presented by the intramolecular cyclization of (25) [89JFC(43)393]. It was found that there was a greater distinction between the two possible sites than when S (i.e., side chain CH=C(C02")S [90JFC(50)229]) was the attacking nucleophile. 

Additionally, it was found that the energy difference between the two transition states (3 and 4) is determined mainly by the difference in the conformational energy of the a-chloro aldehyde in the two transition states i.e., the energetic preference of transition state 3 over 4 is due to a more favorable conformation of the aldehyde rather than a more favorable interaction with the attacking nucleophile. In fact, interaction between lithium hydride and 2-chloropropanal stabilizes transition state 4, which yields the minor diastereomer. 

The overall catalytic rate constant of SNase is (see, for example, Ref. 3) kcat — 95s 1 at T = 297K, corresponding to a total free energy barrier of Ag at = 14.9 kcal/mol. This should be compared to the pseudo-first-order rate constant for nonenzymatic hydrolysis of a phosphodiester bond (with a water molecule as the attacking nucleophile) which is 2 x 10 14 s corresponding to Ag = 36 kcal/mol. The rate increase accomplished by the enzyme is thus 101S-1016, which is quite impressive. 

This is not a new reaction. This is just an Sn2 reaction. We are simply using the alkoxide ion (ethoxide in this case) to function as the attacking nucleophile. But notice the net result of this reaction we have combined an alcohol and an alkyl halide to form an ether. This process has a special name. It is called the Williamson Ether Synthesis. This process relies on an Sn2 reaction as the main step, and therefore, we must be careful to obey the restrictions of Sn2 reactions. It is best to use a primary alkyl halide. Secondary alkyl halides cannot be used because elimination will predominate over substitution (as seen in Sections 10.9), and tertiary alkyl halides certainly cannot be used. 

The alcoholysis and transamination of various aminophosphines have been studied as functions of the basicity of the attacking nucleophile and the substituents on phosphorus. As might be expected the reaction is facilitated by electron-withdrawing groups on phosphorus. The hydrolysis of tris(dimethylamino)phosphine (90) to phosphorous acid has been investigated using thin-layer chromatography and the amides (91) and (92) have been identified as intermediates. 

Deacylation is the reverse of acylation in which a water molecule is the attacking nucleophile (Fig. 11.2b). 

Figure 3.9 An azlactone reacts with amine groups through a ring-opening process, creating amide bond linkages with the attacking nucleophile.

The observed normal isotope effect of 1.9 provides further evidence supporting the role of Asp55 as the general base. Namely, a normal isotope effect of 1.9 is most consistent with general base catalysis by an amino acid side chain, as inverse isotope effects are commonly observed when a zinc-bound water molecule, or hydroxide, is the attacking nucleophile. For example, the zinc-containing enzymes AMP deaminase [111], thermolysin [112], stromelysin [113], and a desuccinylase [114] are each believed to utilize a zinc-bound water as the nucleophile, and all of these reactions are characterized by an inverse deuterium isotope effect. This inverse isotope effect is thought to result from a dominant... 

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 ... 

FIGURE 2.15 Peptide-bond formation from l-ethoxycarbonyl-2-ethoxy-l,2-dihydroquino-line-mediated reactions of A-alkoxycarbonylamino acids.46 The intermediate is the mixed anhydride that is slowly generated in the presence of the attacking nucleophile without a tertiary amine having been added. 

The serine hydrolases, threonine hydrolases, and cysteine hydrolases, the attacking nucleophile of which is a serine or threonine OH group or a cysteine thiolate group, respectively, and which form an intermediate covalent complex (i. e., the acylated enzyme). Here, an activated H20 molecule enters the catalytic cycle in the second step, i.e., hydrolysis of the covalent intermediate to regenerate the enzyme. 

The mechanism of hydrolysis of cysteine peptidases, in particular cysteine endopeptidases (EC 3.4.22), shows similarities and differences with that of serine peptidases [2] [3a] [55 - 59]. Cysteine peptidases also form a covalent, ac-ylated intermediate, but here the attacking nucleophile is the SH group of a cysteine residue, or, rather, the deprotonated thiolate group. Like in serine hydrolases, the imidazole ring of a histidine residue activates the nucleophile, but there is a major difference, since here proton abstraction does not appear to be concerted with nucleophilic substitution but with formation of the stable thiolate-imidazolium ion pair. Presumably as a result of this specific activation of the nucleophile, a H-bond acceptor group like Glu or Asp as found in serine hydrolases is seldom present to complete a catalytic triad. For this reason, cysteine endopeptidases are considered to possess a catalytic dyad (i.e., Cys-S plus H-His+). The active site also contains an oxyanion hole where the terminal NH2 group of a glutamine residue plays a major role. 

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