Nucleophilic aliphatic substitution mechanisms

There are four principal mechanisms for aromatic nucleophilic substitution. Each of the four is similar to one of the aliphatic nucleophilic substitution mechanisms discussed in Chapter 10. 

Several distinct mechanisms are possible for aliphatic nucleophilic substitution reactions, depending on the substrate, nucleophile, leaving group, and reaction conditions. In all of them, however, the attacking reagent carries the electron pair with it, so that the similarities are greater than the differences. Mechanisms that occur at a saturated carbon atom are considered first. By far the most common are the SnI and Sn2 mechanisms. 

Many theories have been put forward to explain the mechanism of inversion. According to the accepted Hugles, Ingold theory aliphatic nucleophilic substitution reactions occur eigher by SN2 or SN1 mechanism. In the SN2 mechanism the backside attack reduces electrostatic repulsion in the transition state to a minimum when the leaving meleophile leaves the asymmetric carbon, naturally an inversion of configuration occurs at the central carbon atom. 

In contrast with aliphatic nucleophilic substitution, nucleophilic displacement reactions on aromatic rings are relatively slow and require activation at the point of attack by electron-withdrawing substituents or heteroatoms, in the case of heteroaromatic systems. With non-activated aromatic systems, the reaction generally involves an elimination-addition mechanism. The addition of phase-transfer catalysts generally enhances the rate of these reactions. 

These alkylations can be looked upon as aliphatic nucleophilic substitutions, usually thoughtto proceed via SnI, Sn2, or hybrids of these mechanisms. However, in recent years more and more evidence for a single-electron transfer (SET) mechanism, represented in Eqs. (28-31), was obtained, and it was suggested that Sn2 and SET are just limiting cases of the same single-electron transfer mechanism [205, 206]. The S ET pathway involves first a transfer of an electron from the nucleophile to the electrophile followed by bond formation, whereas the Sn2 reaction involves a... 

The essential features of the mechanism for aliphatic nucleophilic substitution at tertiary carbon were established in studies by Hughes and Ingold." ° However, as chemists probed more deeply, the problems associated with the characterization of borderline reaction mechanisms were encountered, and controversy remains to this day about whether these problems have been entirely solved." What is generally accepted is that ferf-butyl derivatives undergo borderline solvolysis reactions through a ferf-butyl carbocation intermediate that is too unstable to diffuse freely through nucleophilic solvents such as methanol and water. The borderline nature of substitution reactions at tertiary carbon is exemplihed by the following observations. 

Comprehensive reviews of S 2 substitution can be found in (a) S. R. Hartshorn, Aliphatic Nucleophilic Substitution, Cambridge University Press, London, 1973 (b) A. Streitwieser, Solvolytic Displacement Reactions, McGraw-Hill, New York, 1962 (c) C. K. Ingold, Structure and Mechanism in Organic Chemistry, 2nd ed., Cornell University Press, Ithaca, N.Y., 1969. 

Hughes and Ingold, in 1935. went on to postulate that these mechanisms, or a combination of them in which the nucleophile plays an intermediate role in the departure of-the lea dtux rmiip are general for all aliphatic nucleophilic substitutions.6... 

The first step involves the formation of a pyridinium ion by reaction of a pyrylium ion with a primary amine the second step (dequaternization) has been studied more extensively than the first (amine + pyrylium). This important work on dequaternization deserves special mention because, besides the value for synthesis and understanding of steric acceleration, it sheds new light on the mechanism of aliphatic nucleophilic substitution (84CSR47). 

The author believes that students are well aware of the basic reaction pathways such as substitutions, additions, eliminations, aromatic substitutions, aliphatic nucleophilic substitutions and electrophilic substitutions. Students may follow undergraduate books on reaction mechanisms for basic knowledge of reactive intermediates and oxidation and reduction processes. Reaction Mechanisms in Organic Synthesis provides extensive coverage of various carbon-carbon bond forming reactions such as transition metal catalyzed reactions use of stabilized carbanions, ylides and enamines for the carbon-carbon bond forming reactions and advance level use of oxidation and reduction reagents in synthesis. 

It is not possible to construct an invariant nucleophilicity order because different substrates and different conditions lead to different orders of nucleophilicity, but an overall approximate order is NH2 > PhaC > PhNH (aryne mechanism) > ArS > RO > R2NH > ArO > OH > ArNHi > NH3 > 1 > Br > Cl > H2O > ROH. As with aliphatic nucleophilic substitution, nucleophilicity is generally dependent on base strength and nucleophilicity increases as the attacking atom moves down a column of the periodic table, but there are some surprising exceptions, for example, OH, a stronger base than ArO , is a poorer nucleophile. In a series of similar nucleophiles, such as substituted anilines, nucleophilicity is correlated with base strength. Oddly, the cyanide ion is not a nucleophile for aromatic systems, except for sulfonic acid salts and in the von Richter (13-30) and Rosenmund-von Braun (13-8) reactions, which are special cases. 

For the bimolecular reaction with Ac cleavage, two reasonable mechanisms have been suggested. The first is a direct displacement analogous to the 8 2 mechanism of aliphatic nucleophilic substitution. This route is shown in Eq. (4) structure 2 is the transition state (I), although it is oversimplified because... 

The relative extent of dialkylation depends on the electrophilicity of RX (and the nucleophilicity of AR ) when a realtively fast SET (AE i/2 < 0.5 V) is the primary reaction. Other mechanisms may also satisfactorily explain the distribution of products. For instance, adduct formation between the alkyl radical and the mediator (acting as a radical trap) is possible and must be considered in such a case, further reduction of AR may take place, either by electron transfer or by abstraction of a hydrogen atom from the solvent. However, let us keep in mind that radical anions or dianions may act as nucleophiles, since a partial inversion of configuration of some optically active secondary RX compounds has been found [222] after workup under experimental conditions similar or identical to those of the electrolyses. Table 8 exemplifies alkylation reactions following a SET. The reaction scheme may be complicated by the fact that reduced forms of the mediator may act as a reducing nucleophile toward RX. The SET may then be assumed as the rate-determining step in aliphatic nucleophilic substitutions [223], and/or R generated in solution may be added to an electrophilic mediator, such as an activated ketone [224]. 

The mechanisms that occur in aliphatic electrophilic substitution reactions are less well defined than those that occur in aliphatic nucleophilic substitution and aromatic electrophilic reactions. There is still, however, the usual division between unimolecular and bimolecular pathways the former consisting of only the SE1 mechanism, while the latter consists of the SE2 (front), SE2 (back) and the SEi mechanism. 

The literature (31b, 31c) on aliphatic nucleophilic substitution has drifted from pure SN1 and SN2 to a consideration of borderline mechanisms. Interestingly equation 7 contains within itself the elements needed to cover this borderline region. 

Woodcock, 1968 Collins, 1971 Moss, 1971, 1974 Kirmse, 1976, 1979 Whittaker, 1978, p. 617), but surprisingly only rarely later (briefly by Laali and Olah, 1985, more extensively by Manuilov and Barkhash, 1990). March reviews extensively other aliphatic nucleophilic substitutions in his book Advanced Organic Chemistry (1992), but he makes little reference to deamination mechanisms. 

Mechanism (24) shows significant formal analogies to the 8 2-mechanism in electrophilic aromatic substitution. It has sometimes been denoted as 2-mechanism. This nomenclature is, however, misleading as S 2 was originally introduced by Ingold for that type of aliphatic nucleophilic substitution in which synchronous bond-formation and bond-breaking occur in a single step. 

This chain reaction is analogous to radical chain mechanisms for nucleophilic aliphatic nucleophilic substitution that had been suggested independently by Russell and by Komblum and their co-workers. The descriptive title SrnI (substitution radical-nucleophilic unimolecular) was suggested for this reaction by analogy to the SnI mechanism for aliphatic substitution. The lUPAC notation for the SrkjI reaction is (T -t- Dm -t- An), in which the symbol T refers to an electron transfer. When the reaction was carried out in Ihe presence of solvated electrons formed by adding potassium metal to the ammonia solution, virtually no aryne (rearranged) products were observed. Instead, reaction of 95c produced only 98 (40%) and 94 (40%) but no 99, and reaction of 96c produced 99 (54%) and 94 (30%) with only a trace of 98. ... 

Consider the simple case of an aliphatic nucleophilic substitution carried out in an aqueous-organic two-phase system in the presence of catalytic amoimts of a quaternary ammonium or phosphonium salt Q Y. The detailed mechanism of the reaction, indicated by Eq. (2) as originally proposed by Starks in which and M are the organic and inorganic cations, respectively, involves various factors including ... 

Studies have shown that the HDN of 1,2,3,4-tetrahydroquinoline and 1,2,3,4-tetrahydroisoquinoline catalyzed by sulfided NiMo/Al203 occur via a nucleophilic substitution mechanism [121]. On the other hand, HDN of aliphatic amines with the same catalyst—N1M0/AI2O3—occurs by -elimination [117]. The nature of the base and the amine structure dictate whether the elimination will proceed via a monomolecular (El) or a bimolecular (E2) mechanism. Similarly, for HDN reactions that occur via nucleophilic substitution, these same factors determine if the reaction will follow a monomolecular (Sn 1) or a bimolecular (Sn2) mechanism. 

Aromatic nucleophilic substitution by superoxide occurs by a mechanism different from that encountered in aliphatic nucleophilic substitution reactions of this ion. Thus, reaction of enriched potassium superoxide with l-bromo-2,4-dinitro-benzene catalyzed by dicyclohexyl-18-crown-6 in benzene saturated with unlabeled oxygen results in 2,4-dinitrophenol almost devoid of label. The loss of label in this reaction rules out a direct displacement mechanism. This result is consistent with electron transfer from superoxide anion to the arene to form an intermediate aromatic anion radical which reacts with oxygen (from all sources) to yield phenol. This mechanism is formulated in equation 8.12. Examples of this reaction are presented in Table 8.7. 

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