Nucleophilic substitution

In organic and inorganic chemistry, nucleophilic substitution is a fundamental class of reactions in which an electron rich nucleophile selectively bonds with or attacks the positive or partially positive charge of an atom or a group of atoms to replace a leaving group; the positive or partially positive atom is referred to as an electrophile. The whole molecular entity of which the electrophile and the leaving group are part is usually called the substrate.

Quotes

• Nucleophilic substitution at tetravalent (sp³) carbon is a fundamental reaction of broad synthetic utility and has been the subject of detailed mechanistic study. An interpretation that laid the basis for current understanding was developed in England by C. K. Ingold and E. D. Hughes in the 1930s. Organic chemists have continued to study substitution reactions; much detailed information about these reactions is available and a broad mechanistic interpretation of nucleophilic substitution has been developed from the accumulated data. At the same time, the area of nucleophilic substitution also illustrates the fact that while a broad conceptual framework can outline the general features to be expected for a given system, finer details reveal distinctive aspects that are characteristic of specific systems.
  • Francis A. Carey, ‎Richard J. Sundberg, Ch. 4 "Nucleophilic Substitution" in Advanced Organic Chemistry: Part A: Structure and Mechanisms (2007)

• Aliphatic azides are readily prepared by nucleophilic substitution of alkyl halides or sulfonates with sodium azide; the resulting alkyl azides are readily reduced to primary amines, while 1,3 - dipolar cycloadditions of azide derivatives with dipolarophiles such as alkenes, alkynes, and nitriles give various kinds of azaheterocyclic compounds.
  • Shunsuke Chiba and Koichi Narasaka, "Simple Molecules, Highly Efficient Amination" in Amino Group Chemistry From Synthesis to the Life Sciences Edited by Alfredo Ricci

• In recent years there has been a proliferation of new reactions and reagents that have been so useful in organic synthesis that often people refer to them by name. Many of these are stereo selective or regioselective methods. While the expert may know exactly what the Makosza vicarious nucleophilic substitution, or the Meyers asymmetric synthesis refers to, many students as well as researchers would appreciate guidance regarding such “Name Reactions”.
  • Alfred Hassner and Carol Stumer. Preface to the First Edition of Organic Syntheses Based on Name Reactions

• Alkyl halides are encountered less frequently than their oxygen-containing relatives and are not often involved in the biochemical pathways of terrestrial organisms, but some of the kindsof reactions they undergo— nucleophilic substitutions and eliminations—are encountered frequently. Thus, alkyl halide chemistry acts as a relatively simple model for many mechanistically similar but structurally more complex reactions found in biomolecules.
  • John McMurry, Organic Chemistry (2011), Ch. 10. Organohalides

• Ingold, Hughes, and their collaborators in England, starting in the late 1920s, carried out detailed kinetic and stereochemical investiga tions on what became known as nucleophilic substitution at saturated carbon and polar elimination reactions. Their work relating to uni molecular nucleophilic substitution and elimination, called S_N1 and E1 reactions, in which formation of carbocations is the slow rate determining step, laid the foundation for the role of electron-deficient carbocationic intermediates in organic reactions.
  • George A. Olah, A life of magic chemistry:Autobiographical Reflections of a Nobel Prize Winner (2000)

• Because ML_n consists of an electrophilic metal center and nucleophilic ligands, nucleophilic substitution processes play an important part in the reactivity of complexes.
  • Inorganic Chemistry edited by Egon Wiberg and ‎Nils Wiberg

• Nucleophilic substitution is a fairly general reaction for primary and secondary haloalkanes. The halide functions as the leaving group, and several types of nucleophilic atoms enter into the process.
  • K. Peter C. Vollhardt, Neil E. Schore (2011) Organic chemistry : structure and function 6th ed. Chapter 6. Properties and Reactions of Haloalkanes

• Unhindered primary alkyl substrates always react in a bimolecular way and almost always give predominantly substitution products, except when sterically hindered strong bases, such as potassium tert-butoxide, are employed. In these cases, the S_N2 pathway is slowed down sufficiently for steric reasons to allow the E2 mechanism to take over. Another way of reducing substitution is to introduce branching. However, even in these cases, good nucleophiles still furnish predominantly substitution products. Only strong bases, such as alkoxides, RO^-, or amides, R₂N^-, tend to react by elimination.
  • K. Peter C. Vollhardt, Neil E. Schore (2011) Organic chemistry : structure and function 6th ed. Chapter 7. Further Reactions of Haloalkanes

• Secondary alkyl systems undergo, depending on conditions, both eliminations and substitutions by either possible pathway: uni- or bimolecular. Good nucleophiles favor S_N2, strong bases result in E2, and weakly nucleophilic polar media give mainly S_N1 and E1.
  • K. Peter C. Vollhardt, Neil E. Schore (2011) Organic chemistry : structure and function 6th ed. Chapter 7. Further Reactions of Haloalkanes

• Tertiary systems eliminate (E2) with concentrated strong base and are substituted in nonbasic media (S_N1). Bimolecular substitution is not observed, but elimination by E1 accompanies S_N1.
  • K. Peter C. Vollhardt, Neil E. Schore (2011) Organic chemistry : structure and function 6th ed. Chapter 7. Further Reactions of Haloalkanes

• Another mode of reactivity of carbocations, in addition to regular S_N1 and E1 processes, is rearrangement by hydride or alkyl shifts. In such rearrangements, the migrating group delivers its bonding electron pair to a positively charged carbon neighbor, exchanging places with the charge. Rearrangement may lead to a more stable cation — as in the conversion of a secondary cation into a tertiary one. Primary alcohols also can undergo rearrangement, but they do so by concerted pathways and not through the intermediacy of primary cations.
  • K. Peter C. Vollhardt, Neil E. Schore (2011) Organic chemistry : structure and function 6th ed. Chapter 9. Further Reactions of Alcohols and the Chemistry of Ethers, p. 344

• Nucleophilic substitution at an allylic substrate under S_N2 conditions may proceed via nucleophilic attack at the y-carbon, especially when substitution at the a-carbon sterically impedes the normal S_N2 reaction. These S_N2' reactions with cyclohexenyl systems generally proceed via an anti addition of the nucleophile to the double bond, as depicted below (best overlap of participating orbitals).
  • George S. Zweifel and Michael Nantz, Modern Organic Synthesis (2006), Ch. 2. Stereochemical Considerations in Planning Syntheses