Lone-pair nucleophiles substitutions

Lone-pair nucleophiles are by far the most enthusiastic participants in Sn2 substitution reactions. Sigma-bond nucleophiles may also participate in Sn2 reactions, but they do not do so as often as lone-pair nucleophiles. By contrast, 7r-bond nucleophiles do not usually have sufficiently high energy to react with an atom that already has an octet. The major exceptions to this rule are the enam-ines (R2N-CR=CR2 <—> R2N=CR-CR2), which are sufficiently nucleophilic at the j8 position to attack particularly reactive alkyl halides such as CH3I and al-lylic and benzylic bromides, and enolates (0-CR=CR2 <—> 0=CR-CR2), which react with many alkyl halides. 

The same situation is observed in the series of alkyl-substituted derivatives. Electron-donating alkyl substituents induce an activating effect on the basicity and the nucleophilicity of the nitrogen lone pair that can be counterbalanced by a deactivating and decelerating effect resulting from the steric interaction of ortho substituents. This aspect of the reactivity of thiazole derivatives has been well investigated (198, 215, 446, 452-456) and is discussed in Chapter HI. 

Zahler and elaborated in a series of papers by Miller and co-workers and in Bunnett s publications, many of which are cited in Section I, D. It should be pointed out that the effects of substituents on nucleophilic substitutions show important differences from their effects on other reactions or on equilibria which involve competition for a lone-pair of electrons on another group or stabilization of negative charge on some atom of the reacting moiety. The cr-constants for nucleophilic substitutions differ from those determined in the latter work in that they show the response of the substituent to a strong demand for stabilization of negative charge on the substituent itself, especially by resonance. 

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. ... 

In addition to the effects of a cyclic transition state, of lone-pair repulsions, and of rate of removal of hydride ion mentioned above, the position of nucleophilic substitution can be altered by a) hydrogen... 

Here the nucleophilicity of the dienes was evaluated from the electrostatic potential the energy accounts only for Coulombic interactions, between a test electrophile (a proton) and the dienes. The electrophilicity of the dienophiles was evaluated from electrostatic potential between a test nucleophile (a hydride) and the dienophiles. They stated that, in the case of the reaction of 5-substituted cyclopentadienes, the approach of dienophile (an electrophile) will occur at the syn side of the substituents having lone pairs, and at the anti side of electropositive substituents. There are some... 

Ru—C(carbene) bond distances are shorter than Ru—P bond lengths, but this can simply be explained by the difference in covalent radii between P and The variation of Ru—C(carbene) bond distances among ruthenium carbene complexes illustrates that nucleophilic carbene ligands are better donors when alkyl, instead of aryl, groups are present, with the exception of 6. This anomaly can be explained on the basis of large steric demands of the adamantyl groups on the imidazole framework which hinder the carbene lone pair overlap with metal orbitals. Comparison of the Ru—C(carbene) bond distances among the aryl-substituted carbenes show... 

The formation of 151 from the phosphonate 171 could be proved only by indirect means. Electron-rich aromatic compounds such as N,N-diethylaniline and N,N,N, N -tetraethyl-m-phenylenediamine U0 1I9> and N-methylaniline 120> are phosphorylated in the para- and in the ortho- plus para-positions by 151. Furthermore, 151 also adds to the nitrogen lone pair of aniline to form the corresponding phosphor-amidate. Considerable competition between nucleophiles of various strengths for the monomeric methyl metaphosphate 151 — e.g. aromatic substitution of N,N-diethylaniline and reaction with methanol or aromatic substitution and reaction with the nitrogen lone pair in N-methylaniline — again underline its extraordinary non-selectivity. 

In nucleophilic substitution reactions, the C-X bond of the substrate undergoes heterolysis, and the lone-pair electrons of the nucleophile is used to form a new... 

Steric effects on the nucleophile, aniline, were clearly evident. Rate constants for bimolecular attack of 2,6-dimethyl- 70a, 2,6-diethyl- 70b, and 3,5-dimethylaniline 70c at 308 K indicate that the ort/zo-substituted anilines react more than an order of magnitude slower at the same temperature (Table 7). Structure 70c must be able approach the reactive nitrogen more closely.42,43 A comparison of the rate constants for reaction of aniline 72c, /V-methyl- 71a and /V-phenylaniline 71b provides further evidence of steric effects although the very small rate constant for the diphenylamine could also be accounted for by reduced nucleophilicity on account of lone pair resonance into the additional phenyl ring. 

As the last point in Sect. IV, we discuss briefly the reactions of chiral sulfur compounds with electrophilic reagents. In contrast to nucleophilic substitution reactions, the number of known electrophilic reactions at sulfur is very small and practically limited to chiral tricoordinate sulfur compounds that on reacting with electrophilic reagents produce more stable tetracoordinate derivatives. It is generally assumed that the electrophilic attack is directed on the lone electron pair on sulfur and that the reaction is accompanied by retention of configuration. As typical examples of electrophilic reactions at tricoordinate sulfur, we mention oxidation, imination, alkylation, and halogenation. All these reactions were touched on in the section dealing with the synthesis of chiral tetracoordinate sulfur compounds. 

One explanation for the alpha effect is ground-state de-stabilization Repulsive electronic interactions between the alpha atom s lone-pair and the nucleophile occur in the ground-state, and such destabilization is expected to be relieved as a covalent bond is forming in the transition-state of a nucleophilic substitution reaction. Reduced solvation in molecules exhibiting the alpha effect may also play a role in the increased nucleophilicity for example, OH2 displays no effect in the gas phase, but a substantial effect is observed in solution. Another factor may be the abihty of the alpha lone-pair to stabilize any partially positive group formed in the transition state. 

The Michael addition of nucleophiles to coumarins catalyzed by solid bases provides an interesting approach to the synthesis of 4-substituted 3,4-dihydrocumarins, because with the conventional Michael catalysts the alkaline hydrolysis of the 8-lactone predominates (Scheme 44). Results were obtained when the Michael addition of diethyl malonate to coumarin was catalyzed by the activated Ba(OH)2 292). An unusual 1,2-addition-elimination process at the C = 0 bond was observed. The mechanism of this reaction was explained on the basis of the microcrystalline structure of the catalyst. It was suggested that the rigid coumarin molecule interacts with the Ba ions through the lone-pair electrons of both oxygen atoms of the... 

---