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 → Organometallic Chemistry in Organic Synthesis ↓


Transition metal catalyzed coupling reactions


Transition metal-catalyzed coupling reactions have revolutionized organic synthesis by providing a means of forming carbon-carbon and carbon-heteroatom bonds under mild conditions with high specificity and efficiency. These reactions use transition metals such as palladium, nickel, copper, and rhodium to mediate the formation of bonds between unsaturated organic molecules and organometallic counterparts.

Historical background

The field of transition metal-catalyzed coupling reactions began to flourish in the second half of the 20th century. A key moment was the development of the palladium-catalyzed cross-coupling reaction by Ei-ichi Negishi, Richard F. Heck, and Akira Suzuki, who were awarded the Nobel Prize in Chemistry in 2010 for their work.

Basic principles

Transition metal-catalyzed coupling reactions usually involve the following steps:

  1. Oxidative Additives: A transition metal catalyst enters a bond, forming a metal complex with both bonding partners.
  2. Transmetalation: This step transfers an organic group from a metal source to the central metal atom of the complex.
  3. Reductive elimination: Two organic groups on the metal centre combine to form a new organic compound, regenerating the metal catalyst.

Major reactions

Many named reactions fall under the category of transition metal-catalyzed coupling reactions, each with its own unique starting materials and conditions. Some of the most influential and widely used reactions are as follows:

Suzuki coupling

The Suzuki coupling is a reaction between aryl or vinyl halides and organoboron compounds in the presence of a palladium catalyst and a base. This reaction is highly valued for its tolerance to a wide range of functional groups and its ability to efficiently form carbon-carbon bonds.

Pd-catalyst + base
             ,
R–X + R'–B(OH)2 ———> R–R'

Example: Combination of phenylboronic acid and bromoarine.

C6H5B(OH)2 + Br–C6H4–X → C6H5–C6H4–X + B(OH)3

Heck reaction

The Heck reaction combines alkenes with aryl or vinyl halides. The versatility of this reaction is evident as it combines various olefins with electrophiles in the presence of a palladium catalyst.

Pd Catalyst
   ,
R–CH=CH2 + R'–X ———> R–CH=CH–R'

Example: Coupling of iodobenzene with ethylene.

C6H5I + CH2=CH2 → C6H5–CH=CH2 + HI

Sonogashira coupling

This reaction couples terminal alkynes to aryl or vinyl halides in the presence of a palladium catalyst and a copper co-catalyst. The Sonogashira coupling is particularly notable for the synthesis of aryl acetylene compounds, which are important building blocks in pharmaceuticals and materials.

Pd Catalyst
   ,
R–C≡CH + R'–X ———> R–C≡C–R'

Example: Phenylacetylene with iodobenzene.

C6H5C≡CH + C6H5I → C6H5C≡C–C6H5 + HI

Still coupling

The Stille reaction involves the use of organotin reagents with organic halides in the presence of a palladium catalyst. Due to the stability of organotins, these reagents are often employed in reactions requiring high selectivity.

Pd Catalyst
   ,
R–SNR'3 + R''–X ———> R–R''

Example: Tributylphenyltin reacts with bromobenzene.

C6H5SnBu3 + C6H5Br → C6H5–C6H5 + SnBu3Br

Negishi coupling

Organozinc compounds were initially under-evaluated due to their sensitivity, but the Negishi coupling efficiently employs these compounds, and takes advantage of the variety of available zinc reagents.

Pd Catalyst
   ,
R–Zn–X + R'–X ———> R–R'

Example: Phenylzinc bromide and iodobenzene.

C6H5ZnBr + C6H5I → C6H5–C6H5 + ZnIbr

Mechanistic insights

Understanding these reactions at a mechanistic level increases their utility:

  1. Oxidative Addition: In the initial step the transition metal is inserted into a bond, forming a complex between the metal and the added substrate.
  2. Transmetalation: This step transfers the organic moiety from the metal to the reactive center of the complex, setting the stage for bond formation.
  3. Reductive elimination: Organic groups are coupled to give products, and the metal catalyst is regenerated.

// Example: A simplified catalytic cycle
M -> Oxidative addition -> M(R1)(R2) -> Transmetalation -> M(R1)(R3) -> Reductive elimination -> R1-R3 + M

Catalyst description

Different metals offer unique properties and reactivity profiles:

  • Palladium: Palladium, which plays a key role in these reactions, is versatile and offers high selectivity and yield. It catalyzes several named couplings.
  • Nickel: Nickel is cheaper than palladium and can handle more reactive substrates, but often requires milder conditions.
  • Copper: As a co-catalyst, copper reduces the load on palladium in some reactions, particularly increasing the utility of the Sonogashira coupling.
  • Rhodium: Offers high reactivity and unique selectivity, although it is used less frequently than palladium.

Reagents and conditions

Successful synthesis routes require consideration of the reactivity and stability of the participating reagents:

  • Organohalides: These compounds carry halogens, which are displaced in the formation of new bonds.
  • Organometallic reagents: These compounds include a wide variety of compounds, such as organoborons, organotins, and organozincs, each of which exhibit unique advantages depending on the reactivity.
  • Alkali and solvent: Alkalis such as carbonates or phosphates facilitate the reaction, while solvents such as DMF or THF stabilize the intermediates and improve compatibility.

Applications in organic synthesis

The consequences of coupling reactions are very wide-ranging, allowing to produce the following:

  • Pharmaceuticals: Many drug molecules require multiple coupling reactions in their synthesis, exemplified by the assembly of complex molecular structures essential for biological activity.
  • Agricultural chemicals: The synthesis of insecticides, herbicides, and fungicides often takes advantage of carbon–carbon and carbon–heteroatom bonding structures to produce active compounds.
  • Materials science: Organic electronics and advanced polymers benefit from precise combinations of these reactions, leading to improved conductivity and material properties.

Challenges and growth

Despite his promise:

  • Environmental concerns: Transition metals can be expensive and toxic; therefore, efforts are being made toward developing "green" catalytic processes.
  • Scalability: Coupling reactions must be adaptable from laboratory scale to industrial use, which will require research on supporting technologies.
  • Economical: The metals used are expensive, and optimizing catalyst turnover is essential for practical applications.
In addition, recent studies have focused on:
  • Exploring less common metals such as iron, cobalt, and manganese to broaden the scope of the reaction.
  • Developing ligand designs that increase the speed and selectivity of the reaction.
  • Creating dual metal systems for synergistic benefits.

Conclusion

Transition metal-catalyzed coupling reactions remain a cornerstone of organic chemistry, providing indispensable tools for the construction of complex and diverse molecules. Continued innovations are likely to expand the scope, efficiency, and stability of these reactions, thereby maintaining their important position in organic synthesis.


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Transition metal catalyzed coupling reactions

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