Nucleophilic reactions relative reactivity

Several methods have been employed to extract the rate constant of the addition of nucleophiles to the aryl radicals from the kinetics of Sr I reactions. Relative reactivities of two nucleophiles towards the same aryl radical have been obtained from the ratio of the two substitution products after preparative-scale reaction of the substrate with a mixture of the two nucleophiles under photochemical or solvated-electron induction (Galli and Bunnett, 1981). 

MECHANISM OF NUCLEOPHILIC ACYL SUBSTITUTION Acid-Catalyzed Acyl Substitution Reactions Base-Catalyzed Acyl Substitution Reactions Relative Reactivity of Acyl Derivatives... 

Relative reactivity is A (nucleophile)/A (methanol) for typical Sn2 reactions and is approximate Data pertain to methanol as the solvent... 

Ring substituents show enhanced reactivity towards nucleophilic substitution, relative to the unoxidized systems, with substituents a to the fV-oxide showing greater reactivity than those in the /3-position. In the case of quinoxalines and phenazines the degree of labilization of a given substituent is dependent on whether the intermediate addition complex is stabilized by mesomeric interactions and this is easily predicted from valence bond considerations. 2-Chloropyrazine 1-oxide is readily converted into 2-hydroxypyrazine 1-oxide (l-hydroxy-2(l//)-pyrazinone) (55) on treatment with dilute aqueous sodium hydroxide (63G339), whereas both 2,3-dichloropyrazine and 3-chloropyrazine 1-oxide are stable under these conditions. This reaction is of particular importance in the preparation of pyrazine-based hydroxamic acids which have antibiotic properties. 

Although different reaction types exhibit large quantitative differences, and there are exceptions, the order 5>6>3>7>4> 8-10 is a rough guide of relative reactivity for many systems. Some quantitative data on typical reactions involving nucleophilic substitution or participation are shown in Scheme 3.4. 

Reductions by NaBKt are characterized by low enthalpies of activation (8-13kcal/mol) and large negative entropies of activation (—28 to —40eu). Aldehydes are substantially more reactive than ketones, as can be seen by comparison of the rate data for benzaldehyde and acetophenone. This relative reactivity is characteristic of nearly all carbonyl addition reactions. The reduced reactivity of ketones is attributed primarily to steric effects. Not only does the additional substituent increase the steric restrictions to approach of the nucleophile, but it also causes larger steric interaction in the tetrahedral product as the hybridization changes from trigonal to tetrahedral. 

The lack of a uniform order of relative reactivity of the halogens in reactions of certain nucleophiles with nitro- and polynitro-phenyl halides led Parker and Read to propose a one-stage mechanism for some aromatic nucleophilic substitutions. An alternative explanation within the framework of the two-stage S Ar2 mechanism had been proposed earlier. A range of mechanisms has been considered in the past by Chapman, who properly points out that only in a limited number of examples is the evidence for the two-stage mechanism compelling even though the balance of evidence favors it. 

The effects of the nucleophile on aromatic substitution which are pertinent to our main theme of relative reactivity of azine rings and of ring-positions are brought together here. The influence of a nucleophile on relative positional reactivity can arise from its characteristics alone or from its interaction with the ring or with ring-substituents. The effect of different nucleophiles on the rates of reaction of a single substrate has been discussed in terms of polarizability, basicity, alpha effect (lone-pair on the atom adjacent to the nucleophilic atom), and solvation in several reviews and papers. ... 

Halopyridines undergo self-quaternization on standing while the less reactive 2-halo isomers do not. However, more is involved here than the relative reactivity at the ring-positions. The reaction rate will depend on the relative riucleophilicity of the attack-ing pyridine-nitrogens (4-chloropyridine is more basic) and on the much lower steric hindrance at the 4-position. Related to this self-quatemization are the reactions of pyridine and picolines as nucleophiles with 4-chloro- and 2-chloro-3-nitropyridines. The 4-isomer (289) is. again the more reactive by 10-30-fold (Table VII, p. 276). 

In Scheme IV, intranuclejar activation is depicted. Kinetic studies with ionic nucleophiles show a variable relationship between the rates of reaction ortho and para to an azine-nitrogen (348 vs. 353 or 349) or nitro group due to entropy effects the energy of activation is expected on further study to be consistently lower for the para-position. The relative reactivity of 2- and 4-substituted bicyclic azines... 

Specific alterations of the relative reactivity due to hydrogen bonding in the transition state or to a cyclic transition state or to electrostatic attraction in quaternary compounds or protonated azines are included below (cf. also Sections II, B, 3 II, B, 5 II, C and II, F). A-Protonation is often reflected in an increase in JS and therefore the relative reactivity can vary with the significance of JS in controlling the reaction rate. Variation can also result from rate determination by the second stage of the SjjAr2 mechanism or from the intervention of thermodynamic control of product formation. Variation in the rate and in the reactivity pattern of polyazanaph-thalenes will result when nucleophilic substitution [Eq. (10)] occurs only on a covalent adduct (408) of the substrate rather than on its aromatic form (400). This covalent addition is prevented by any 4-... 

On the basis of the reaction of alkyl radicals with a number of polycyclic aromatics, Szwarc and Binks calculated the relative selectivities of several radicals methyl, 1 (by definition) ethyl, 1.0 n-propyl, 1.0 trichloromethyl, 1.8. The relative reactivities of the three alkyl radicals toward aromatics therefore appears to be the same. On the other hand, quinoline (the only heterocyclic compound so far examined in reactions with alkyl radicals other than methyl) shows a steady increase in its reactivity toward methyl, ethyl, and n-propyl radicals. This would suggest that the nucleophilic character of the alkyl radicals increases in the order Me < Et < n-Pr, and that the selectivity of the radical as defined by Szwarc is not necessarily a measure of its polar character. 

Mixed condensations of esters are subject to the same general restrictions as outlined for mixed aldol reactions (Section 2.1.2). One reactant must act preferentially as the acceptor and another as the nucleophile for good yields to be obtained. Combinations that work best involve one ester that cannot form an enolate but is relatively reactive as an electrophile. Esters of aromatic acids, formic acid, and oxalic acid are especially useful. Some examples of mixed ester condensations are shown in Section C of Scheme 2.14. Entries 9 and 10 show diethyl oxalate as the acceptor, and aromatic esters function as acceptors in Entries 11 and 12. 

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