Organometallic Synthesis and Chemistry

Organometallic synthesis, or organometallic chemistry, represents a broad scope of use in synthetic organic chemistry. Organometallic synthesis refers to the process of creating organometallic compounds. 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 synthesis of a number of commercial compounds used in the pharmaceutical, polymer, and petrochemical industries.

Organometallic is a molecule that contains a metal atom bonded to a carbon atom. Compounds with, for example, metal-nitrogen, metal-oxygen, metal-phosphorus bonds are defined as coordination complexes but are often described as organometallic. Organometallic compounds may contain group 1 alkali, group 2 alkali earth, group 3-12 transition, and 13-15 main group elements, as well as metalloids, such as boron and silicon. The large array of elements that can form organometallic compounds result in vast research in procedures for organometallic synthesis. There are also research efforts in the use of organometallic reagents in the synthesis of ever-more complex and tailored organic compound, for which organometallic reagents drive specific bonding and/or catalyze reactions. 

There are numerous other ways to synthesize organometallics:

• One of the most used methods to synthesize an organometallic compound is to react the pure metal with specific organic molecules. Examples of this type of synthesis are two of the most frequently used organometallic reagents, organolithium and organomagnesium, for which the metal is reacted with an alkyl- or aryl-halide to form the desired reagent.
  
  
• In double-decomposition reactions, metal halides exchange with alkylating reagents to yield the organometallic reagent. Carbon monoxide reacts with transition metals to form metal carbonyls.
  
  
• Decarbonylation of a metallo-organic will produce an organometallic compound.
  
  
• Hydrometalation is a synthesis method in which a molecule with a metal -hydrogen bond reacts with an organic molecule containing a double bond, forming a organometallic with a metal-carbon bond.

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

Organometallic reagents are frequently used to synthesize organic molecules since they drive specific bonding and/or catalyze reactions. Some of these reactions are difficult or impractical to carry out by other means. In most organic compounds, carbon atoms tend to be electrophilic, but in organometallic compounds, because the metal atom is typically less electronegative than the carbon it is attached to, the carbon acts as a nucleophile of varying strength. When a strongly electronegative metal is involved, the charge distribution is such that the compound is more ionic in nature and can be strongly reactive. 

For example, in organolithium compounds the C-Li bond is more ionic and the C is more negatively polarized. The bonds in organolithium compounds are more strongly polarized than in their organomagnesium analogs (Grignard reagents), making organolithium a stronger nucleophile and more reactive compared to the Grignard. Both organomagnesium and organolithium reagents are strong bases for deprotonation and readily form C-C bonds, as well as drive many other organic reactions.

Organometallic compounds are widely used is catalytic chemistry. A classic example is the use of chlorotris (triphenylphosphine) rhodium to reduce alkenes and alkynes - without affecting other functional groups in a molecule. Another family of organometallic-based catalysts with Josiphos diphosphine ligands are used for enantioselective hydrogenation reactions. Hydrogenation and hydroformylation reactions are industrially important reactions that are catalyzed by various organorhodium or organocobalt compounds. Polymerization reactions are performed using catalysts, such as Ziegler-Natta compounds, which are two-part catalysts often containing Ti and Al that polymerize olefins.

The number of organometallic compounds is vast and cover most of the major elements in the periodic groups. Most examples of organometallics are either in the main group elements or the transition group elements. In the former group, bonding is more ionic or sigma bonded. The classic examples are organolithium or organomagnesium compounds, both of which are important in organic synthesis. Higher ionic bonding results in a more reactive compound. In the transition group elements, bonding is typically more covalent and complex as compared to the main group elements. Metal-alkyl, -alkene, and -alkyne and metal aryl groups such as benzene are often bonded with transition elements. Bonding in these compounds are strong with delocalized pi bonding contributions.

Examples of important organometallics include organolithium, organoborane (period 2 elements), organomagnesium, organosilicon (period 3 elements), organoiron, organocobalt (period 4 elements), organoruthenium, organotin (period 5 elements), organoplatinum, organoiridium (period 6 elements).

Organometallic compounds are highly reactive and typically have very fast reactions. Working with organometallic compounds, including lithium-aluminum hydride, lithium borohydride, diisobutylaluminium hydride, and Grignard reagents, requires tight temperature control at low temperatures. Consequently, reactions with organometallic compounds are often run at temperatures between 0° and -78°C to control the reaction and:

• Obtain the Right Product
• Assure Selectivity
• Avoid Side-Reactions, the Formation of By-Products, or Decomposition
• Ensure Reaction Control and Safety

Traditionally, syntheses that include such components are cooled using cooling baths with dry ice and an organic solvent, or possibly a large and bulky cryostat. The use of cooling mixtures is a challenge since there is no flexibility in regard to temperature, and constant observation is required. The cooling liquids used are typically organic solvents, such as ethanol, acetone, cyclohexane, cyclohexanone, or isopropanol. All of them pose a safety risk since they are flammable. Organic solvents can also be expensive. Therefore, traditional cooling mixtures have limitations.

EasyMaxchemical synthesis reactors, which offer calorimetric capability, are used in pharmaceutical and chemical development laboratories to optimize reaction variables, for faster scale-up, measuring reaction thermodynamics, and process safety. The automated laboratory reactor is optimal to support Design of Experiments studies and other methods that mathematically relate experimental parameters and performance.

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FTIR spectroscopy is one of the fundamental analysis methods used to the investigate organometallic compounds. Charge distribution and dipole strength of metal – carbon bonding is one of main markers for reactivity and a key reason why organometallics have such usefulness in chemistry. Infrared spectroscopy is uniquely sensitive to changes in dipole moments, and thus gives great insight into bonding. Complex metal-ligand bonding in transition metal complexes is another area where FTIR excels at providing structural information. Infrared spectra give relative information about the length of bonds and strength of bonding. For example, infrared is frequently used to investigate carbonyl bonding with transition metals, since depending on the position of the carbonyl as well as if it is a bridging carbonyl, there are indicative peak frequency changes that directly relate to bond strength.

Raman spectroscopy is also used for investigation of organometallic synthesis and structure, as well as studying metallo-organo synthesis. In addition to fingerprint region spectral information, Raman spectroscopy is well-suited to measure lower frequency vibrations that are often observed in metal-containing organic compounds and in metal-metal bonding. Also, there is substantial interest in organometallic chemistry carried out in aqueous solution in advancing “green chemistry”. As an example, molybdocenes are useful for carbonyl reductions in aqueous solution. Raman is the ideal choice for studying molecular bonding in aqueous media.

EasySampler automated sampling implements a unique method of in-situ capturing, quenching, and preparing each sample for offline measurements. This unattended and automated sampling technology enables taking a representative sample within air- and moisture-sensitive, heterogeneous, and highly-reactive organometallic chemistry. C-C and C-N coupling reactions in organometallic synthesis, such as Ullmann and Buchwald-Hartwig, reveal how organometallic reactions can be monitored using EasySampler in-situ sampling.

ReactIR and ReactRaman have all the aforementioned benefits of the basic techniques, along with additional advantages of real-time, in-situ measurement. This enables investigating reactions as a function of time and under actual reaction conditions. Both techniques can be applied to batch or flow synthesis reaction.

As in classic organic chemistry, the ReactIR/ReactRaman technology provides detailed information about reaction kinetics, mechanisms, and insight into the presence and identity of transient intermediates. Since organometallic chemistry is often carried out under varied reaction conditions such as low or elevated temperature, elevated pressure and/or in the absence of oxygen and water vapor, the ability to measure chemistry without manually removing a sample for analysis is critical. Since many organometallic compounds are highly toxic, in situ analysis is important for ensuring lab safety. 

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• Study organometallic synthesis under actual reaction conditions
• Track reactants and reagents as a function of time
• Measure reaction trends and progress
• Identify key intermediate species including transients
• Determine organometallic reaction kinetics and mechanism
• Determine structure of organometallic compounds, including intermediates
• Gain insight into metal-ligand bonding and ligand disassociation
• Develop thorough understanding of metallo-organic synthesis kinetics/mechanism
• Investigate organometallic reactions in all solvents including water
• Measure important lower frequency metal vibrations
• Measure reactions though glass reactor vessels
• Eliminate manual sampling and unnecessary exposure to toxic compounds
• Suitable for batch and flow syntheses

Individually, or as an integrated chemical workstation, these tools provide critical support for better organometallic synthesis reactions:

• FTIR Spectrometers and Raman Spectrometers
  Real-time tracking and profiling of key reaction species as a function of reaction time to aid kinetics and mechanistic investigations
• Automated, Inline Sampling (EasySampler)
  Unattended, representative sampling of reactions when offline analysis is required
• Chemical Synthesis Reactors (EasyMax and OptiMax)
  Unattended, precise control, and data collection of reaction conditions
• Reaction and Heat Flow Calorimeters (RC1mx and HFCal)
  Measure complete heat of reaction to ensure safety by design

The EasyMax LT (LowTemp) was specifically developed for applications that require reaction temperatures between RT and -80° C - without compromising on accuracy, precision, fast response, or cooling performance to heat release during a reaction.

Experiments can be pre-programmed, run automatically, and unattended. Data from online analytics or sampling tools are collected and can be integrated into the data, recipes, or annotations collected during the experiment and used for experiment evaluation and reporting.

• Paul Brunel, Chloé Lhardy, Sonia Mallet-Ladeira, Julien Monot, Blanca Martin-Vaca, Didier Bourissou, “Palladium pincer complexes featuring an unsymmetrical SCN indene-based ligand with a hemilabile pyridine sidearm” , Dalton Trans., 2019, 48, 9801-9806.
• Kori A. Andrea, Tyler R. Brown, Jennifer N. Murphy, Dakshita Jagota, Declan McKearney, Christopher M. Kozak, Francesca M. Kerton, “Characterization of Oxo-Bridged Iron Amino-bis(phenolate) Complexes Formed Intentionally or in Situ: Mechanistic Insight into Epoxide Deoxygenation during the Coupling of CO2 and Epoxides”, Inorganic Chemistry 2018, 57, 21, 13494-13504.
• Zackary R. Gregg, Justin R. Griffiths, Steven T. Diver, “Conformational Control of Initiation Rate in Hoveyda–Grubbs Precatalysts”, Organometallics, 2018, 37, 10, 1526-1533.
• Justin R. Griffiths, Elan J. Hofman, Jerome B. Keister, Steven T. Diver, “Kinetics and Mechanism of Isocyanide-Promoted Carbene Insertion into the Aryl Substituent of an N-Heterocyclic Carbene Ligand in Ruthenium-Based Metathesis Catalysts", Organometallics 2017, 36, 16, 3043-3052.
• Ross J.Beattie, Peter S. White, Joseph L. Templeton, “Formation of [(CO)(HCCH)Tp'W=NCH(CH3)CH(CH3)N=WTp'(HCCH)(CO)][I3]2 by oxidation of Tp'W(CO)(HCCH)(NCHCH3) and radical dimerization”, J. Organometallic Chem. 2017, 847, 54-58.
• Wen-Bo Liu, David P. Schuman, Yun-Fang Yang, Anton A. Toutov, Yong Liang, Hendrik F. T. Klare, Nasri Nesnas, Martin Oestreich, Donna G. Blackmond, Scott C. Virgil, Shibdas Banerjee, Richard N. Zare, Robert H. Grubbs, K. N. Houk, Brian M. Stoltz, “Potassium tert-Butoxide-Catalyzed Dehydrogenative C–H Silylation of Heteroaromatics: A Combined Experimental and Computational Mechanistic Study”, J. Amer. Chem. Soc., 2017, 139, 20, 6867-6879.
• Ben Cheng, Hong Yi, Chuan He, Chao Liu, Aiwen Lei, “Revealing the Ligand Effect on Copper(I) Disproportionation via Operando IR Spectra”, Organometallics 2015, 3, 41, 206-211.
• Alexander F. R. Kilpatrick, Jennifer C. Green, F. Geoffrey N. Cloke, “The Reductive Activation of CO2 Across a Ti═Ti Double Bond: Synthetic, Structural, and Mechanistic Studies”, Organometallics 2015, 34, 20, 4816-4829.
• Alexander F. R. Kilpatrick, Jennifer C. Green, F. Geoffrey N. Cloke, “ Bonding in Complexes of Bis(pentalene)dititanium, Ti2(C8H6)2”, Organometallics 2015, 34, 4830−4843.
• Ryan D. Bethel, Danielle J. Crouthers, Chung-Hung Hsieh, Jason A. Denny, Michael B. Hall, Marcetta Y. Darensbourg, “Regioselectivity in Ligand Substitution Reactions on Diiron Complexes Governed by Nucleophilic and Electrophilic Ligand Properties”, Inorg. Chem. 2015 5, 47, 3523-3535.

Wen-Bo Liu, David P. Schuman, Yun-Fang Yang, Anton A. Toutov, Yong Liang, Hendrik F. T. Klare, Nasri Nesnas, Martin Oestreich, Donna G. Blackmond, Scott C. Virgil, Shibdas Banerjee, Richard N. Zare, Robert H. Grubbs, K. N. Houk, and Brian M. Stoltz, “Potassium tert-Butoxide-Catalyzed Dehydrogenative C−H Silylation of Heteroaromatics: A Combined Experimental and Computational Mechanistic Study”, J. Am. Chem. Soc. 2017, 139, 6867−6879.

In this in-depth study, the researchers investigated the mechanism by which potassium tert-butoxide catalyzes the dehydrogenative coupling of heteroarenes with hydrosilanes to form heteroarylsilanes, which in turn are intermediates that can be used build more complex molecules. As part of this effort, researchers used ReactIR FTIR Spectroscopy to investigate the possible presence of a coordinated silane species. In related research by other groups, it was shown that the reaction of (RO)3SiH with the corresponding KOR (R = alkyl or aryl) results in fivecoordinate hydridosilicate [HSi(OR)4]K. The researchers in this work postulated an analogous pentacoordinated intermediate for their reaction, but NMR studies were unsuccessful at providing confirmation. They report, however, evidence for this pentacoordinate species by monitoring the silylation reaction with ReactIR. The spectrum of this reaction revealed a new peak (2056 cm-1) adjacent to the Si-H stretching band in Et3SiH (2100 cm-1). They postulated this peak is consistent with the elongated Si−H bond, as expected in such pentacoordinate complexes. They also observed that the new peak correlated with silylation product formation and postulated that the formation of penta coordinate silicate is responsible for the observed induction period in the reaction.