Organometallics | API Synthesis | Organometallic Chemistry

Overview of organometallic compounds & organometallic reactions for the organic synthesis of Active Pharmaceutical Ingredients (APIs), HPAPIs, etc.

Q1. What is organometallic chemistry?

Organometallic chemistry is the study of the synthesis, structure and reactivity of chemical compounds that contain metal-carbon bonds. Applied organometallic chemistry is useful for chemical synthesis, especially catalytic processes known as organometallic catalysis, often used in the production of fine chemicals. The field has provided a series of important conceptual insights, surprising structures, and useful organometallic catalysis reactions, both for industrial processes and for organic synthesis.

Organometallics, with their metal–carbon bonds, lie at the interface between classical organic and inorganic chemistry in dealing with the interaction between inorganic metal species and organic molecules. Usually, organometallic compounds are composed not only of typical metals, but also of metalloids such as boron, silicon, phosphorus, arsenic, selenium, etc.

Applied organometallic chemistry is among the most actively researched areas in organic, inorganic, biochemical, and catalytic chemistry. This arises from the use of organometallic reagents in the organometallic synthesis of a number of commercial compounds used in the pharmaceutical, polymer, and petrochemical industries. Without these organometallic reagents and catalysts, many of the existing synthetic manufacturing methods would be economically infeasible.

Some of the key points in the fast expansion of organometallic chemistry are the selectivity of organometallic complexes in organic synthesis (discovered with Grignard reagents at the end of the 19th century), and the interesting role that metals play in biological systems (e.g. enzymes, hemoglobin, etc.).

Types of Organometallic Chemistry Reactions (or Organometallic Reactions):

- Ligand dissociation/ligand association

- Reductive elimination/oxidative addition

- Alpha bond metathesis/4-centered reaction

- Insertion/deinsertion

- Lewis acid activation of electrophile

Q2. What are organometallic compounds?

Organometallic compounds have been known and studied for over 250 years. Many of these early compounds were prepared directly from metals by the oxidative addition of alkyl halides.

Organometallic compounds provide a source of nucleophilic carbon atoms which can react with electrophilic carbon atoms to form a new carbon-carbon bond. This is very important for advanced organic synthesis and the practical and scalable organometallic synthesis of complex molecules from simple starting materials.

Furthermore, all metals used in organometallic compounds have strong or moderately negative reduction potentials, with lithium and magnesium being the most reactive, and are consequently used as homogeneous catalysts.

Organometallic compounds have played a critical role in organometallic catalysis and organic synthesis, often leading to more efficient use of reagents, higher yields of products, and lower usage of energy. Organometallic compounds have also been used as precursors in the preparation of nanomaterials and microelectronic materials.

The physical and chemical properties of organometallic compounds vary greatly:

- Most are solids, particularly those whose hydrocarbon groups are ring-shaped or aromatic, but some are liquids and some are gases.

- Their heat and oxidation stability vary widely. Some are very stable, but a number of compounds of electropositive elements such as lithium, sodium, and aluminum are spontaneously flammable.

- Many organometallic compounds are highly toxic, especially those that are volatile.

Organometallic compounds have a broad range of applications in the field of applied organometallic chemistry:

- In some commercial, chemical reactions for the advanced organic synthesis or organometallic synthesis of chemical compounds, organometallic compounds are used as homogeneous catalysts.

- These compounds are used as stoichiometric organometallic reagents in both industrial and research-oriented advanced organic synthesis or custom organic synthesis and manufacturing.

- They also facilitate the protection and stabilization of unsaturated organic fragments

Q3. How are organometallic compounds synthesized?

There are various methods to synthesize organometallics, some of these are noted below:

Organometallic Reactions of Metals with Organic Halides

One of the most used methods to synthesize organometallics is to react the pure metal with specific organic molecules. The reaction of a metal with an organic halide is a convenient method for preparation of organometallic compounds of reasonably active metals such as lithium, magnesium, and zinc.

Double-decomposition Organometallic Reactions

A double decomposition reaction is a reaction in which the positive ions and negative ions in two compounds switch partners to form two new compounds. Metal halides exchange with alkylating reagents to yield organometallic reagents. Carbon monoxide reacts with transition metals to form metal carbonyls.

Decarbonylation of a Metallo-organic

Decarbonylation organometallic reactions involve the removal of one or more carbonyl groups from a metallo-organic molecule. The decarbonylation of metallo-organic compounds (chemical compounds that contain metals and organic ligands) will produce organometallics or organometallic compounds.

Hydrometalation Organometallic Reactions

Hydrometallation is the addition reaction of a metal hydride to a double bond (triple bond) to form an organometallic compound.

Various addition and elimination reactions form organometallic compounds from metallo-organic molecules. Choosing the optimal organometallic synthesis method is often informed by inline analytical techniques to ensure safe and efficient process development.

Q4. Who are the different service providers offering organometallic services?

Service providers offering organometallic services include:

Sanofi Active Ingredient Solutions

SAIS is an organometallic API CMO service provider. They offer organometallic services, advanced organic synthesis CMO capabilities & cGMP manufacturing of organometallic compounds by multistep reactions for active pharmaceutical ingredient (API) manufacturing.

PMC Isochem

Over 40 years PMC Isochem has developed a versatile technology platform offering cyanation for active pharmaceutical ingredients (APIs) and intermediates, biocatalysis, enzymatic catalysis, alkylation, hydrogenation, organometallic services (organometallic synthesis), halogenation and phosgenation for intermediate and API manufacturing.

Zach System

Zach provides custom API synthesis and manufacturing services for active pharmaceutical ingredients (API) & quality intermediates. They offer the following organometallic services: Metal hydride reduction, reductive amination, grignard reagents, cryogenic carbanionic chemistry and mild and catalytic C-C bond forming reactions.

Minakem

Minakem is capable of undertaking a broad range of multi-steps syntheses in organic chemistry. Their key technologies for active pharmaceutical ingredient (API) manufacturing include cyanidation, hydrogenation, high pressure reactions, chiral chemistry, hazardous chemistry & continuous flow chemistry.

Polpharma

Polpharma offers several complex chemistry & analytical services including organometallic chemistry, chiral, stereo and regioselective synthesis, catalytic hydrogenation, amino acids and peptide chemistry, polymorphism and solid state chemistry.