Reaction Mechanisms of Nucleophilic Substitutions

The different resonance structures represent a Meisenheimer complex. The loss of the leaving group reestablishes the stable aromatic system. 

Unlike the positively charged sigma complex, the Meisenheimer complex has a negative charge. 

Nucleophilic substitution occurs only when the benzene ring is activated by a strong electron-withdrawing group. 

Losing and Gaining Mechanisms of Eiimination/Addition Reactions 

A traditional 8, 1 or S, 2 mechanism doesn t work for aromatic systems, so a new mechanism is necessary. This new mechanism is the Sj Ar or addition-elimination mechanism. Like an S, 2 mechanism, an Sj Ar mechanism begins with the attack of the nucleophile. After the initial attack the mechanism is quite different. 

The Sj,j2 mechanism is a one-step process in which a nucleophile attacks the substrate, and a leaving group, L, departs simultaneously. Because the reaction occurs in one step, it is concerted. The substrate and the nucleophile are both present in the transition state for this step. Because two molecules are present in the transition state, the reaction is bitnolecular, as indicated by the number 2 in the Sj 2 symbol. The rate of an Sj 2 reaction is first order in the substrate and first order in the nucleophile. If the substrate concentration is doubled, the reaction rate doubles. Similarly, if the concentration of the nucleophile is doubled, the rate again doubles. This relationship between the rate and the concentration of the reactants exists because the reactants must collide for reaction to occur. The probability that the nucleophile will collide with the substrate increases if the concentration of either species is increased or if the concentrations of both are increased. 

As hydrogen atoms are replaced one by one going from a methyl group to a tertiary halide, the reaction becomes slower because the nucleophile cannot easily reach the electrophilic carbon of the substrate. The electron density maps for these alkyl halides show this effect. The rate of an Sj 2 reaction decreases in the order methyl primary secondary tertiary. 

In fact, for a tertiary center, the Sj 2 mechanism is not observed. Instead, the mechanism changes from Sj 2 to Sj l, as we will shordy discover. Regions colored in red have high electron density. 

An Sj 2 reaction occurs in living cells in which a methyl group is transferred from a methylating agent called 5-adenosylmethionine (SAM) to various biological substrates, including nucleic acids, proteins, and many metabolic intermediates. 

An important example of methyl group transfer from SAM to a nucleophile occurs in the biosynthesis of the neurotransmitter epinephrine. In this reaction, an amino group of norepinephrine attacks the methyl group of 5-adenosyhnethionine in an S 2 reaction to produce epinephrine. The leaving group is 5-adenosylhomocysteine, the compound diat results from the loss of a methyl group from 5-adenosylmethionine. 

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In addition to steric effects, there are other important substituent effects which determine both the rate and mechanism of nucleophilic substitution reactions. It was... 

Figure 3.14 Mechanism of nucleophilic substitution reactions of lignin during sulfite pulping.

Organic chemistry and instrumental analysis Synthesis 3 Mechanisms of nucleophilic substitution reactions... 

Going over the basics and mechanisms of nucleophilic substitution reactions Mastering mechanisms of elimination/addition reactions Determining synthesis strategies for aromatic systems... 

The importance of understanding the mechanism of nucleophilic substitution reactions can best be appreciated by studying the distribution of products of the example given above. When 2-bromopropane is allowed to react with the methoxide ion in methanol, less than half of the starting material is converted into methyl isopropyl ether the rest is transformed into 2-propene. 

Nucleophilic substitution reactions on unactivated alkyl halides have been known for a long time. The available mechanisms depend on the aliphatic moiety, the nucleophile, the leaving group and the reaction conditions118. Besides the polar mechanisms of nucleophilic substitution reactions (S l, S 2 and related mechanisms), several alkyl halides react with nucleophiles by an ET reaction. 

That is, the act of shifting the single electron from Y to X may occur either with or without free-radical formation. Usually, the concerted non-radicaloid process is energetically favoured. For a more detailed discussion of the various mechanisms of nucleophilic substitution reactions in aliphatic compounds and their solvent dependence, see references [14, 483, 782-785]. 

Silicon compounds with coordination number larger than four are the object of many studies first with respect to their application as catalysts in organic and inorganic syntheses and second as starting materials for the preparation of a broad variety of organosilicon compounds [1]. Additionally, hypervalent silicon hydride compounds can successfully be used as model compounds to study, for instance, the mechanism of nucleophilic substitution reactions, which is of great interest since the silicon atom is able to easily extend its coordination number [1]. Moreover, hypervalent silanes are suitable as starting materials for the synthesis and stabilization of low-valent silanediyl transition metal complexes [2-5]. 

In addition to steric effects, there are other important substituent effects that influence both the rate and mechanism of nucleophilic substitution reactions. As we discussed on p. 302, the benzylic and allylic cations are stabilized by electron delocalization. It is therefore easy to understand why substitution reactions of the ionization type proceed more rapidly in these systems than in alkyl systems. Direct displacement reactions also take place particularly rapidly in benzylic and allylic systems for example, allyl chloride is 33 times more reactive than ethyl chloride toward iodide ion in acetone." These enhanced rates reflect stabilization of the Sjv2 TS through overlap of the /2-type orbital that develops at carbon." The tt systems of the allylic and benzylic groups provide extended conjugation. This conjugation can stabilize the TS, whether the substitution site has carbocation character and is electron poor or is electron rich as a result of a concerted Sjv2 mechanism. 

Let us now begin to consider the mechanisms of nucleophilic substitution reactions. How does the nucleophile replace the leaving group Does the reaction take place in one step or is more than one step involved If more than one step is involved, what kinds of intermediates are formed Which steps are fast and which are slow In order to answer these questions, we need to know something about the rates of chemical reactions. 

Domingos, J.B., Longhinotti, E., Brandao, T.A.S., Bunton, C.A., Santos, L.S., Eber-lin, M.N., Nome, F. (2004) Mechanisms of Nucleophilic Substitution Reactions of Methylated Hydroxylamines with Bis(2,4-dinitrophenyl)phosphate. Mass Spectro-metric Identification of Key Intermediates. J. Org. Chem. 69 6024-6033. 

As a result of experiments that began more than 70 years ago, we now understand the mechanisms of nucleophilic substitution reactions rather well. We use the plural because such nucleophilic substitutions occur by more than one mechanism. The mechanism observed in a particular case depends on the structures of the nucleophile and the alkyl halide, the solvent, the reaction temperature, and other factors. 

Another interesting approach using ESI(—)-MS was used to probe the mechanism of nucleophilic substitution reactions of methylated hydroxylamines, hydrazine and hydrogen peroxide with bis(2,4-dinitrophenyl)phosphate (BDNPP) [86]. ESI-MS screening of the reaction was performed to fish ionic intermediates and products directly from solution into the gas phase, and the key intermediates were fully... 

Mechanisms of Nucleophilic Substitution Reactions in Octahedral Complexes 141... 

MECHANISMS OF NUCLEOPHILIC SUBSTITUTION REACTIONS IN OCTAHEDRAL COMPLEXES... 

Scheme 5. Mechanism of nucleophilic substitution reaction carried out under phase transfer conditions.

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