Nucleophilicity sequence, for substitution

This is called the nucleophilicity sequence for substitution at square planar Pt(II) and the ordering is consistent with Pt(II) being a soft metal centre (see Table 6.9). A nucleophilicity parameter, Kpt, is defined by equation 25.19 where kf is the rate constant for reaction 25.18 with Y = MeOH (i.e. for Y = MeOH, npt = 0). 

For substituted anilines (Thompson and Williams, 1977) and for 1-naphthylamine and a series of derivatives thereof (Castro et al., 1986a), k2 and the ratio Ar 2/Ar3 have been determined for nucleophilic catalysis with Cl-, Br-, SCN-, and SC(NH2)2. The values of k2 correspond fairly well to those found for the diazotization of aniline, but those of Ar 2/Ar3 increase markedly in the above sequence (Table 3-1). As k3 is expected to be independent of the presence of Cl- or Br- and to show little dependence on that of SCN- or thiourea, the increase in k 2/k3 for this series must be due mainly to 2. Indeed, the value of log(Ar 2/Ar3) shows a linear correlation with Pearson s nucleophilicity parameter n (Pearson et al., 1968). This parameter is based on nucleophilic substitution of iodine (as I-) in methyl iodide by various nucleophiles. The three investigations on nucleophilic catalysis of diazotization demonstrate that Pearson s criteria for bimolecular nucleophilic substitution at sp3 carbon atoms are also applicable to substitution at nitrogen atoms. 

Scheme 2.125. Twofold elimination/nucleophilic substitution sequence for the synthesis of 2-554.

The carbonyl groups that participate in the alkyne-addition process have not been limited to those that can form enol tautomers. For example, amides have been used as nucleophiles in a one-pot reaction sequence for the preparation of 2,3-disubstituted furanopyridones using Pd catalysis (Equation (96)).343 Furopyridines have also been obtained from the reaction of iodopyridones with alkynes under Pd catalysis,344 and alkynyl pyrimidones have been converted into 2-substituted furanopyrimidones under the influence of an AgN03 catalyst.345... 

Only very powerful nucleophilic reagents such as HO-, NHJ, RLi, LAH, etc., react effectively at the ring carbon atoms of simple pyridines (c/. equation 22), and even then forcing conditions may be required. Oxidation of pyridine to 2-pyridone with potassium hydroxide, for example, requires a temperature of ca. 300 °C. Nevertheless, some of these reactions can be of very considerable synthetic importance, especially the classical Chichibabin reaction for the preparation of 2-amino, alkylamino and hydrazino heterocycles (equation 28). The sequence of substitution is C-2, then C-6 and finally C-4. The Chichibabin reaction also requires rather vigorous conditions and often proceeds in only moderate yield the simplicity of the approach, however, is such that it often represents the method of choice for the preparation of the requisite substituted heterocycle. 

Vinyl ethers and amines disclose little tendency to revert to type thus, the intermediate formed by reaction with an electrophilic reagent reacts further by adding a nucleophilic species to yield an addition compound cf the sequence (8) — (11). Thiophene and pyrrole have a high degree of aromatic character consequently the initial product formed by reaction of thiophene or pyrrole with an electrophilic species subsequently loses a proton to give a substituted compound cf the reaction sequence (12) — (15). Furan has less aromatic character and often reacts by overall addition as well as by substitution. In electrophilic addition, the first step is the same as for substitution, i.e. the formation of a tr-complex (e.g. 13), but instead of losing a proton this now adds a nucleophile. 

In order to learn how to generate a complete mechanistic sequence for a complex reaction, we consider now a nucleophilic substitution reaction of esters, amides and so on, shown in Equation 6.23,... 

Whereas electrophilic attack of benzene is both well known and important, the corresponding reaction with nucleophiles is very difficult and is not typical of aromatic compounds. However, if the aromatic ring is TT-electron deficient because an electron-withdrawing group (EWG) is present, then nucleophilic attack can occur. The mechanism for the addition-elimination sequence for nucleophilic substitution is shown in Scheme 2.17. 

Early attempts to establish mechanistic models for substitution at metal centers used the labels Sjp and SN2 (substitution, nucleophilic, unimolecular or bimolecular) inherited from Ingold s attempts26 to extend his classic studies in organic reaction mechanisms to substitution at elements other than carbon. Unfortunately, Ingold s attribution of the discontinuity in reaction rates in the replacement of one Cl in m-Co(en)2CI2 1 by various anions A in methanol in the sequence... 

Spontaneous hydrolyses of sulfonyl chlorides are believed to involve nucleophilic attack in the rate-limiting step although questions arise as to the timing of the bond-making and -breaking steps, because attack of water and loss of Cl- could be concerted or stepwise (66-68). The rate sequence for reactions of para-substituted benzenesulfonyl chlorides in water is H3CO > CH3 > H > Br < N02. 

There is an alternate mechanism for substitution, following the sequence of nucleophile addition, protonation, and elimination of HX. In this pathway, the addition of the nucleophile need not be at the ipso position it can be ortho to halide leading to cine substitution or it can be at the meta (in 24) or para positions, leading to tele" substitution via elimination of HX from an intermediate such as 25 [2,46]. The processes depend on the formation of the cyclohexadi-enyl anion intermediates (24) in a favorable equilibrium (carbon nucleophiles from carbon acids with pKa>22 or so), followed by protonation (which can occur at low temperature with even weak acids such as acetic acid), and hydrogen shifts in the proposed diene-chromium intermediates (26) [46]. Hydrogen shifts lead to an isomer (25) which allows elimination of HX and regeneration of an arene-chromium complex, now with the carbanion unit indirectly substituted for X. 

A number of dialkyl sulfides were identified in an aquifer polluted from a waste-water tank of a chemical plant that manufactured a range of alkyl halides. This observation indicated that nucleophiles other than water and OH could be active in the environment. Sulfur is widely distributed and under reducing conditions hydrogen sulfide can be produced. This acid has a pAia of 7.0 and the bisulfide ion (HS ) would predominate at basic pH values. Laboratory studies with bromohexane demonstrated that the bisulfide ion could compete with water in substitution reactions. A reaction sequence for the production of dialkyl sulfides is as follows ... 

This route is especially convenient because no over-alkylation of the anion of acetonitrile occurs. Over-alkylation can be a problem in attempts to methylate the anion of diethyl cyano-methylphosphonate (4) directly a mixture of unalkylated, monoalkylated and dialkylated products in a ratio of 1 2 1 is formed. The same problem arises with the alkylation of triethyl phosphonoacetate (11). For the preparation of a Ca-ester synthon, an alternative method to the propionitrile route is used (Scheme 7). This method has been used in the synthesis of labelled Cio-central units, described in the next Section. The starting material is acetic acid (9) which is converted into ethyl bromoacetate (10) as described above (Scheme 3). The ethyl bromoacetate (10) is reacted with triphenyl phosphine in a nucleophilic substitution reaction the phosphonium salt is formed (yield 97%). The phosphonium salt is deprotonated in a two-layer system of dichloromethane and an aqueous solution of NaOH. After isolation, the phosphorane 22 is reacted at room temperature with one equivalent of methyl iodide (19) the product consists mainly of the monomethylated phosphonium salt (>90%) which is deprotonated with NaOH, to give the phosphorane 23 in quantitative yield relative to phosphorane 22, and 23 is reacted with the aldehyde in dichloromethane. The ester product 12 can subsequently be reduced to the corresponding alcohol and reoxidized to the aldehyde 8. An alternative two-step sequence for this has also been used. First, the ester 12 is converted into the A -methyl-iV-methoxyamide (16) quantitatively by allowing it to react with the anion of A, 0-dimethylhydroxylamine as described above (Scheme 5). This amide 16 is converted, in one step, into the aldehyde 8 by reacting it with DIB AH in THF at -40°C [46]. 

As for the pentacyano-complexes just dealt with, nucleophilic substitution at low-spin iron(ii) di-imine complexes, [Fe(LL)3], appears in this section as well as in the chapters on base hydrolysis and ligand replacement. Schiff-base di-imine ligands such as (1) are unsymmetrical, with non-equivalent iron-nitrogen bonds in their complexes. There is thus the possibility of two simultaneous paths for the aquation of such complexes. Kinetic parameters for the various paths and steps in the reaction sequence for aquation of the complex of (I ... 

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