Graduate
  1. Physical Chemistry  1.1. Thermodynamics  1.1.1. Laws of Thermodynamics  1.1.2. Enthalpy and heat capacity  1.1.3. Entropy and free energy  1.1.4. Phase Equilibrium  1.1.5. Statistical thermodynamics  1.1.6. Thermodynamic cycle  1.1.7. Fugacity and activity  1.2. Quantum Chemistry  1.2.1. Principles of quantum mechanics  1.2.2. Schrödinger Equation  1.2.3. Particle in a box  1.2.4. Operators and eigenvalues  1.2.5. Atomic orbitals  1.2.6. Molecular orbital theory  1.2.7. Perturbation theory  1.2.8. Valence bond theory  1.2.9. Hybridization and chemical bonding  1.3. Chemical kinetics  1.3.1. Rate laws and reaction mechanisms  1.3.2. Collision theory  1.3.3. Transition state theory  1.3.4. Enzyme Kinetics  1.3.5. Chain Reactions and Polymerization  1.3.6. Photochemical reactions  1.4. Statistical mechanics  1.4.1. Partitioning functions  1.4.2. Molecular distribution functions  1.4.3. Boltzmann Distribution  1.4.4. Bose–Einstein and Fermi–Dirac statistics  1.5. Spectroscopy  1.5.1. Rotational Spectroscopy  1.5.2. Vibrational Spectroscopy  1.5.3. Electronic Spectroscopy  1.5.4. Nuclear magnetic resonance spectroscopy  1.5.5. Mass Spectrometry  1.5.6. Raman Spectroscopy  1.5.7. Electron paramagnetic resonance spectroscopy  1.6. Surface and colloidal chemistry  1.6.1. Absorption isotherm  1.6.2. Surface tension and wetting  1.6.3. Colloidal Stability  1.6.4. Catalysis  1.6.5. Emulsions and micelles  1.7. Electrochemistry  1.7.1. Nernst equation  1.7.2. Electrochemical cells  1.7.3. Conductivity and mobility  1.7.4. War  1.7.5. Fuel cells  1.7.6. Electrolysis
  2. Organic chemistry  2.1. Reaction mechanism  2.1.1. Nucleophilic substitution reactions  2.1.2. Electrophilic addition reactions  2.1.3. Elimination reactions  2.1.4. Rearrangement reactions  2.1.5. Radical reactions  2.1.6. Pericyclic reactions  2.2. Spectroscopy and structural determination  2.2.1. UV-Vis Spectroscopy  2.2.2. IR Spectroscopy  2.2.3. NMR Spectroscopy  2.2.4. Mass Spectrometry  2.2.5. X-ray crystallography  2.3. Stereoscopic  2.3.1. Chirality and optical activity  2.3.2. Structural analysis  2.3.3. Geometrical isomerism  2.3.4. Dynamic Stereochemistry  2.4. Organometallic Chemistry  2.4.1. Organolithium and organomagnesium reagents  2.4.2. Palladium-catalyzed cross-coupling reactions  2.4.3. Transition Metal Complexes  2.4.4. Metal–carbon bond  2.5. Polymer chemistry  2.5.1. Polymerization mechanism  2.5.2. Polymer Characteristics  2.5.3. Biodegradable Polymer  2.5.4. Conducting polymer  2.5.5. Supramolecular polymers  2.6. Medicinal chemistry  2.6.1. Drug design and development  2.6.2. Pharmacokinetics and pharmacodynamics  2.6.3. Structure-activity relationships  2.6.4. Molecular docking and drug screening
  3. Inorganic chemistry  3.1. Coordination chemistry  3.1.1. Crystal field theory  3.1.2. Ligand field theory  3.1.3. Spectrochemical Series  3.1.4. Chelation and stability  3.2. Organometallic Chemistry  3.2.1. Metal Carbonyls  3.2.2. Catalysis by organometallic complexes  3.2.3. Metallocenes  3.3. Bio-inorganic chemistry  3.3.1. Metalloproteins and enzymes  3.3.2. The role of metals in biological systems  3.3.3. Metal ion transport and storage  3.4. Solid state chemistry  3.4.1. Crystal Structures  3.4.2. Band theory of solids  3.4.3. Superconductors  3.4.4. Defects in the crystal  3.5. Lanthanides and Actinides  3.5.1. Electronic configuration in lanthanides and actinides  3.5.2. Coordination chemistry of the lanthanides  3.5.3. Magnetic Properties of Lanthanides
  4. Analytical chemistry  4.1. Chromatography  4.1.1. Gas Chromatography  4.1.2. High Performance Liquid Chromatography  4.1.3. Thin Layer Chromatography  4.2. Spectroscopic Techniques  4.2.1. Atomic absorption spectroscopy  4.2.2. X-ray diffraction  4.2.3. Inductively coupled plasma spectroscopy  4.3. Electroanalytical methods  4.3.1. Potentiometry  4.3.2. Voltammetry  4.3.3. Colometry  4.4. Mass Spectrometry  4.4.1. Ionization Technique  4.4.2. Fragmentation Pattern  4.5. Chemometrics  4.5.1. Multidisciplinary analysis  4.5.2. Machine Learning in Chemistry
  5. Theoretical and Computational Chemistry  5.1. Molecular dynamics simulation  5.1.1. Force fields and energy minimization  5.1.2. Monte Carlo simulation in molecular dynamics simulations  5.2. Quantum chemical methods  5.2.1. Hartree–Fock theory  5.2.2. Density functional theory  5.2.3. Semi-empirical methods  5.3. Computational drug design  5.3.1. Molecular Docking  5.3.2. QSAR Modeling  5.3.3. Virtual Screening
  6. Biochemistry  6.1. Enzyme Kinetics  6.1.1. Michaelis-Menten kinetics  6.1.2. Inhibition mechanism  6.2. Metabolism and Bioenergetics  6.2.1. Glycolysis  6.2.2. Citric acid cycle  6.2.3. Electron transport chain  6.3. molecular Biology  6.3.1. DNA replication and repair  6.3.2. Protein synthesis  6.3.3. Gene Regulation  6.4. Structural Biochemistry  6.4.1. Protein Folding  6.4.2. Membrane Biophysics
  7. Environmental Chemistry  7.1. Atmospheric Chemistry  7.1.1. Greenhouse gases  7.1.2. Ozone depletion  7.1.3. Air pollutants and smoke  7.2. Water Chemistry  7.2.1. pH and water hardness  7.2.2. Wastewater treatment  7.2.3. Aquatic Chemistry  7.3. Soil Chemistry  7.3.1. Heavy metal contamination  7.3.2. Soil pH and Buffering  7.3.3. Nutrient cycling  7.4. Toxicology and Chemical Safety  7.4.1. Toxicokinetics  7.4.2. Risk Assessment in Toxicology and Chemical Safety in Environmental Chemistry  7.4.3. Effects of pollutants on the environment

Graduate → Organic chemistry → Organometallic Chemistry ↓


Palladium-catalyzed cross-coupling reactions


Palladium-catalyzed cross-coupling reactions are a cornerstone in the field of organic synthesis and constitute a powerful method for creating carbon-carbon and carbon-heteroatom bonds. This topic is of vital importance due to its utility in creating complex molecules, including pharmaceuticals, natural products, and advanced materials.

Introduction to cross-coupling reactions

Cross-coupling reactions involve the coupling of two different types of molecular fragments, forming a new chemical bond. This process is typically facilitated by a transition metal catalyst, with palladium being one of the most effective. The general mechanism involves catalytic activation, oxidative addition of an electrophile, transmetalation with a nucleophile, and a sequence of reductive eliminations to form the product and regenerate the catalyst.

Basic mechanism of palladium-catalyzed cross-coupling

Palladium-catalyzed cross-coupling typically follows a three-step process:

1. Oxidative Yoga
2. Transmetalation
3. Reductive elimination

1. Oxidative Yoga

In the oxidative addition step, palladium(0), which is usually a Pd(0) complex, interacts with an electrophilic organohalide. This forms a palladium(II) complex, leaving the metal center partially oxidized. The mechanism can be represented as follows:

Pd(0) + RX → R-Pd(II)-X

Where RX represents organic halide or pseudohalide.

2. Transmetalation

The transmetallation step involves the exchange of ligands between two metals. In the context of cross-coupling, this often involves organometallic reagents such as organoboron or organozinc compounds. The process can be described as follows:

R-Pd(II)-X + R'-M → R-Pd(II)-R' + MX

Here, R'-M is usually the organometallic reagent, and it shares R' group with the palladium complex.

3. Reductive elimination

The final step, reductive elimination, results in the formation of the desired carbon–carbon bond, regenerating the palladium(0) species. A simplification of this step is as follows:

R-Pd(II)-R' → RR' + Pd(0)

Common palladium-catalyzed cross-coupling reactions

There are several well-known palladium-catalyzed cross-coupling reactions, each named after its discoverer. Some of the most important of these are:

Suzuki–Miyaura coupling

R-Br + R'-B(OH)2 + Pd(0) → RR' + HX

Here, an organoboron compound couples with an organohalide in the presence of a palladium catalyst to form a biaryl or other biphenyl derivative. This reaction is particularly valuable for its tolerance to a variety of functional groups and mild conditions.

R-Br R'-B(OH) 2 + Pd(0) R-R'

Heck reaction

RX + CH=CH-R' + Pd(0) → R-CH=CH-R' + HX

In the Heck reaction, alkenes are combined with organohalides. This reaction produces substituted alkenes, which are often used in complex organic synthesis.

Rx CH=CH-R' + Pd(0) R-CH=CH-R'

Negishi coupling

RX + R'-ZnX + Pd(0) → RR' + ZnX 2

Negishi coupling is a powerful method using organozinc reagents. These reagents provide chemoselectivity that is difficult to achieve with other metal complexes.

Stille coupling

RX + R'- SnBu3 + Pd(0) → RR' + Bu3Sn -X

In this reaction, organotin compounds serve as nucleophilic partners, allowing the coupling of a wide variety of functional groups.

Pd sources and ligands

Selecting the right catalyst and ligand is essential for a successful palladium-catalyzed cross-coupling reaction. Palladium catalysts are typically used in the form of complexes such as the following:

Pd(PPh 3) 4
PD(OAC) 2
PDCL 2

The choice of ligand can significantly affect the reactivity and selectivity of the catalyst. Common ligands include:

  • Ph 3 P - triphenylphosphine
  • BINAP - chiral bisphosphine ligand
  • DPPF - Bis(diphenylphosphino)ferrocene

The ligands help stabilize the palladium complex and can also fine-tune the electronic and static properties of the catalytic center.

Factors affecting cross-coupling reactions

Several factors can affect the efficacy of palladium-catalyzed cross-coupling reactions:

  1. Scope of substrate: Type of halide (Cl, Br, I), with iodo being more reactive than chloro.
  2. Solvent: The choice of solvents can largely affect turnover frequency and selectivity.
  3. Temperature: Coupling reactions often require specific temperature conditions to proceed efficiently.

Optimization of these factors is crucial for achieving high yields and selectivity.

Stereochemistry and regioselectivity

The stereochemistry of the product is an essential consideration. Reactions such as the Stille and Suzuki couplings are particularly valuable for their ability to maintain the stereochemical integrity of the substrate.

Regioselectivity refers to precise control over the atom or functional group participating in the coupling. Selection of catalysts and reaction conditions can enable a high degree of regioselectivity, which is important for the synthesis of complex molecules.

Application

Palladium-catalyzed cross-coupling reactions have a wide range of applications:

  • Pharmaceuticals: Essential in the synthesis of active pharmaceutical ingredients (APIs).
  • Agricultural chemicals: Useful in the production of insecticides and herbicides.
  • Materials science: Creation of organic materials with advanced properties (e.g., OLEDs).

Challenges and innovations

Despite their widespread use, palladium-catalyzed cross-couplings are not devoid of challenges, including:

  • Cost: Palladium is an expensive metal, and its recovery is important.
  • Environmental concerns: The ligands and organometallic reagents used can cause waste disposal problems.

Innovative advances are being made to address these challenges, such as the discovery of iron and nickel catalysts, which may offer cheaper and less toxic alternatives. Additionally, the development of environmentally friendly ligands and reagents remains an active research area.

Conclusion

The importance of palladium-catalyzed cross-coupling reactions in modern organic chemistry is enormous. These reactions provide a robust and versatile method for constructing a wide range of molecular structures. Continuing research and innovation promise to expand the horizons of these reactions, making them even more applicable in various fields of science and technology.


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Palladium-catalyzed cross-coupling reactions

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