PHD
  1. Inorganic chemistry  1.1. Coordination chemistry  1.1.1. Ligand field theory  1.1.2. Crystal field theory  1.1.3. Molecular Orbital Theory for Coordination Compounds  1.1.4. Stability of Coordination Compounds  1.1.5. Electronic spectra of coordination compounds  1.1.6. Isomerism in Coordination Compounds  1.1.7. Kinetics and mechanism of coordination reactions  1.2. Organometallic Chemistry  1.2.1. Metal Carbonyls  1.2.2. Metal alkyl and aryl  1.2.3. Fischer and Schrock carbonaceans  1.2.4. Oxidative Addition and Reductive Elimination  1.2.5. Metal Hydrides  1.2.6. Catalysis by organometallic compounds  1.2.7. Metallocenes and Sandwich Complexes  1.2.8. CH activation  1.3. Solid state chemistry  1.3.1. Crystal structures and lattices  1.3.2. Band theory and electrical properties  1.3.3. Defects in the crystal  1.3.4. Synthesis of solid state materials  1.3.5. Magnetic and optical properties of solids  1.3.6. Superconductivity  1.3.7. Solid state ionics  1.4. Bio-inorganic chemistry  1.4.1. Metalloproteins and enzymes  1.4.2. Metal ion transport and storage  1.4.3. The role of metals in medicine  1.4.4. Bioinspired catalysis  1.4.5. Metal–DNA interactions  1.4.6. Metal Complexes in Medical Science  1.5. Lanthanides and Actinides  1.5.1. Electronic configuration and oxidation states in lanthanides and actinides  1.5.2. Spectral and Magnetic Properties in Lanthanides and Actinides  1.5.3. Separation and Extraction of Lanthanides and Actinides  1.5.4. Coordination chemistry of f-block elements  1.6. Main Group Chemistry  1.6.1. Chemistry of boron compounds  1.6.2. Chemistry of Silicon and Germanium Compounds  1.6.3. Chemistry of Phosphorus and Sulfur Compounds  1.6.4. Organosilicon chemistry  1.6.5. Noble Gas Chemistry
  2. Organic chemistry  2.1. Reaction mechanism  2.1.1. Nucleophilic substitution reactions  2.1.2. Electrophilic addition and substitution reactions  2.1.3. Elimination reactions  2.1.4. Rearrangement reactions  2.1.5. Radical reactions  2.1.6. Pericyclic Reactions  2.1.7. Photochemical reactions  2.2. Stereoscopic  2.2.1. Chirality and optical activity  2.2.2. Structural analysis  2.2.3. Stereoelectronic effects  2.2.4. Asymmetric synthesis  2.2.5. Dynamic Stereochemistry  2.3. Organometallic Chemistry in Organic Synthesis  2.3.1. Organolithium and organomagnesium reagents  2.3.2. Transition metal catalyzed coupling reactions  2.3.3. Palladium-catalyzed reactions  2.3.4. Olefin Metathesis  2.3.5. Gold and silver catalysis  2.4. Natural products chemistry  2.4.1. Alkaloids and terpenoids  2.4.2. Steroids and Flavonoids  2.4.3. Total synthesis of natural products  2.4.4. Biosynthesis of natural products  2.5. Supramolecular Chemistry  2.5.1. Host-Guest Chemistry  2.5.2. Self-assembly and molecular recognition  2.5.3. Supramolecular Catalysis  2.5.4. Molecular Machines
  3. Physical Chemistry  3.1. Thermodynamics  3.1.1. Laws of Thermodynamics  3.1.2. Chemical Potential and Equilibrium  3.1.3. Statistical thermodynamics  3.1.4. Non-equilibrium thermodynamics  3.2. Quantum Chemistry  3.2.1. Schrödinger equation and its applications  3.2.2. Molecular orbital theory  3.2.3. Density functional theory  3.2.4. Post-Hartree–Fock methods  3.3. Chemical kinetics  3.3.1. Reaction rate theory  3.3.2. Mechanism and rate laws  3.3.3. Catalysis and enzyme kinetics  3.3.4. Reaction dynamics  3.4. Spectroscopy and molecular structure  3.4.1. Infrared Spectroscopy  3.4.2. UV-visible spectroscopy  3.4.3. Nuclear Magnetic Resonance Spectroscopy  3.4.4. Mass Spectrometry  3.4.5. Raman Spectroscopy  3.5. Surface and Colloid Chemistry  3.5.1. Absorption and Catalysis  3.5.2. Surfactants and micelles  3.5.3. Colloidal Stability  3.5.4. Nanomaterials and Interfaces
  4. Analytical chemistry  4.1. Chromatography  4.1.1. Gas Chromatography  4.1.2. High Performance Liquid Chromatography  4.1.3. Thin Layer Chromatography  4.1.4. Ion Chromatography  4.2. Electroanalytical techniques  4.2.1. Voltammetry and Polarography  4.2.2. Conductometry and potentiometry  4.2.3. Colometry  4.3. Spectroscopic Methods  4.3.1. Atomic absorption spectroscopy  4.3.2. Fluorescence Spectroscopy  4.3.3. X-ray diffraction  4.3.4. Electron paramagnetic resonance spectroscopy  4.4. Chemometrics  4.4.1. Data processing and statistical methods  4.4.2. Multidisciplinary analysis  4.4.3. Machine Learning in Analytical Chemistry
  5. Theoretical and Computational Chemistry  5.1. Molecular dynamics simulation  5.2. Quantum chemistry methods  5.3. Computational drug design  5.4. Machine Learning in Chemistry  5.5. Ab initio molecular dynamics
  6. Biophysics and Medicinal Chemistry  6.1. Drug discovery and design  6.2. Enzyme kinetics and inhibition  6.3. Chemical biology approach  6.4. Protein-ligand interactions  6.5. Bioorthogonal chemistry
  7. Materials chemistry  7.1. Polymer chemistry  7.1.1. Polymerization mechanism  7.1.2. Functional Polymers  7.1.3. Biodegradable Polymer  7.1.4. Conducting and semiconducting polymers  7.2. Nano Chemistry  7.2.1. Nanoparticles and nanostructures  7.2.2. Carbon-based nanomaterials  7.2.3. Quantum dots  7.3. Energy and Environmental Chemistry  7.3.1. Battery and Fuel Cell Chemistry  7.3.2. Green chemistry and sustainable materials  7.3.3. Photocatalysis

PHD → Organic chemistry → Reaction mechanism ↓


Nucleophilic substitution reactions


Nucleophilic substitution reactions are fundamental processes in organic chemistry known for their role in replacing an atom or group of atoms in a molecule with another atom or group. This topic is important because of its applicability in understanding synthesis and reaction mechanisms. In nucleophilic substitution reactions, the molecule undergoing substitution is generally called the substrate or electrophile, and the species bringing about the substitution is called the nucleophile.

Basic concepts

At the core of nucleophilic substitution reactions, the nucleophile is typically an electron-rich species, characterized by the presence of unshared electron pairs or a negative charge. They are attracted to electron-deficient centers due to their electron richness. Electrophiles, in this context, are molecules containing positively polarized atoms, often due to the presence of leaving groups. Leaving groups are atoms or groups, such as halides or tosylates, that can easily dissociate from the substrate, allowing the nucleophile to bind.

Visual representation of nucleophilic substitution

New: R-LG LG (1) Nucleophilic attack (2) Group leaves

Mechanistic pathway: SN1 and SN2 reactions

Nucleophilic substitution reactions can occur mainly via two mechanisms: SN1 and SN2 pathways. "SN" denotes "substitution nucleophilic", and the number indicates the kinetic order of the reaction.

SN1 reactions

The SN1 mechanism, or unimolecular nucleophilic substitution, involves a two-step process with one intermediate. Let's go through these steps:

  1. Carbocation formation: The leaving group is abstracted from the substrate, forming a carbocation, an intermediate where the central carbon atom has a positive charge: 
    R-LG → R+ + LG-
    This phase is usually slow and determines the rate of the reaction.
  2. Nucleophilic attack: The nucleophile attacks the carbocation, resulting in the final substituted product: 
    R+ + Nu: → R-Nu
    This completes the fast phase reaction.

Because of the formation of intermediates, SN1 reactions typically lead to a mixture of products if the substrate is chiral, potentially resulting in racemization due to the non-planar intermediate geometry.

SN2 reactions

In contrast, the SN2 mechanism, or bimolecular nucleophilic substitution, proceeds via a single coordination step:

Nu: + R-LG → [Nu---R---LG]‡ → R-Nu + LG-

Here, the nucleophile attacks the substrate from the opposite direction to the leaving group, producing a pentacoordinate transition state. Simultaneous bond formation and breaking leads to an inversion of configuration, known as Walden inversion.

SN2 reactions are sensitive to steric factors; bulky groups around the reactive center can hinder the approach of the nucleophile, making SN2 reactions less viable.

New: R LG LG (1) Nucleophilic attack - backwards

Factors affecting the nucleophilic substitution mechanism

Several factors affect whether a reaction proceeds via the SN1 or SN2 mechanism. These include:

  • Substrate structure: Tertiary carbons favor SN1 reactions due to stable carbocation formation, while primary substrates are more favorable for SN2 mechanism due to less steric hindrance.
  • Nucleophile strength: Strong, negatively charged nucleophiles tend toward the SN2 pathway, while weak nucleophiles are more common in SN1 reactions.
  • Ability of the leaving group: A good leaving group is essential for both mechanisms, but is more important for SN1 reactions where the leaving step is rate-determining.
  • Solvent effect: Polar protic solvents stabilize the ions and favor SN1 pathways, while polar aprotic solvents increase nucleophilicity, favoring SN2 mechanisms.

Examples and applications

Consider the substitution reaction of bromide with hydroxide in methyl bromide, an SN2 reaction:

CH3 Br + OH- → CH3 OH + Br-

In this example, the hydroxide ion, a strong nucleophile, attacks the carbon opposite the bromine, resulting in the formation of methanol and a bromide ion. The sterically unshielded methyl substrate favors the SN2 pathway.

An example of an SN1 reaction is the hydrolysis of tert-butyl chloride in water:

(CH3)3 CCl + H2 O → (CH3)3 COH + HCl

Here, the elimination of chloride leads to the formation of a stable tertiary carbocation, which reacts with water to form tertiary-butyl alcohol. The polar and protic nature of water facilitates SN1 conditions.

Advanced ideas

The study of nucleophilic substitution extends into hybrid scenarios where both SN1 and SN2 mechanisms can compete, a phenomenon that depends on the specific reaction conditions and molecular structures. Additionally, some substrates can undergo substitution via SNAR (aromatic nucleophilic substitution) or neighboring group participation, where atoms near the reaction center participate to stabilize the intermediate.

For example, when allylic or benzylic systems are considered, resonance can stabilize the carbocation, changing the mechanism of the reaction from pure SN2 to a more complex hybrid one. In some cases, solvent systems can be manipulated to toggle between pathways, providing tools for selective synthesis.

Using isotopic labeling and computational chemistry, organic chemists can trace the internal energy profiles and intermediates involved in these reactions, providing insight into the microscopic mechanical transformations.

Conclusion

Nucleophilic substitution reactions are quintessential to the field of organic chemistry, providing mechanisms that underpin a great deal of synthetic strategies. By understanding the nuances between the SN1 and SN2 pathways, chemists can predict and influence reaction outcomes, harnessing such reactions to develop pharmaceuticals, materials, and a variety of organic compounds. Furthermore, as research uncovers more complex details about molecular reactivity, the scope of nucleophilic substitution as an important concept in chemistry continues to grow.


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Nucleophilic substitution reactions

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