C-H Activation Reactions

C-H bond activation is a series of mechanistic processes by which stable carbon-hydrogen bonds in organic compounds are cleaved. The purpose is to enable functionalization of these molecules, leading to the synthesis of more complex intermediate or product compounds often containing C-0, C-C and C-N bonds. The ability to cleave the C-H bond enables inexpensive feedstock molecules to be transformed into commercially valuable molecules. Directed C-H activation enables selectivity and specificity in the synthesis of more complex molecules of importance in pharmaceutical and fine chemical applications.

There are a number of mechanisms by which C-H bonds are activated including oxidative addition, σ-Bond metathesis, electrophilic substitution, etc. By definition, C-H activation occurs via catalytic mechanisms.  As an example, C-H activation occurs when transition metals such as Pt, Rh, Ir, etc. are used in catalytic oxidative addition reactions. A proton attached to a carbon atom on the substrate hydrocarbon molecule coordinates with the transition metal to form an intermediate organometallic species. This intermediate can the react with other species to form the functionalized carbon bond. C-H cleavage and functionalization can proceed stoichiometrically, for example using Friedel-Craft chemistry via electrophilic aromatic substitution. C-H activation/borylation of substrate molecules via transition metals is particularly useful to create C-B bonds.  Organoboron compounds are used in cross-coupling reactions, which make them important in the formation of C-C bonds.   

Biocatalytic, electrocatalytic and photocatalytic reactions as well as hybrid techniques, such as photobiocatalysis and photoelectrocatalysis, are increasingly used to activate C-H bonds. This is associated with the interest in C-H activation under milder conditions and using Earth-abundant metal catalysts for more sustainable approaches to chemical synthesis.  Furthermore, C-H activation under milder conditions enables the synthesis of molecular functionality that would not be tolerant of the harsher reaction conditions of thermal chemocatalysis.

C-H bond activation and functionalization is of intense interest in organic synthesis, and the development of catalysts to enable activation of C-H bonds are likewise intensely researched.  The drivers for this work are that C-H activation enables relatively simple hydrocarbons to be effectively converted into more complex molecules.  The benefits include better atom efficiency and overall economics, reactions can potentially be performed under milder conditions with less toxic or expensive reactants, and functional group positional selectivity is enhanced.  These advantages make C-H activation desirable for the formation of C-C bonds when compared to more classic methods such as cross-coupling reactions.

The development of catalysts for performing C-H activation span the transition metals and the oxidation state, associated ligands and electron availability define mechanism and pathways.   As an example, high valent metals such as Pd(II), Rh(III), Ir(III), Ru(II)  react via electrophilic pathways whereas low valent, electron-rich metals such as Rh(I) or Ir(I) proceed by oxidative addition in C-H activation reactions.   Directed C-H activation targets specific C-H bonds and can be used, in one example, in ortho metalation and functionalization of aromatic hydrocarbons. Whether a metal atom is chelated or coordinated drives functional groups positional selectivity. 

When considering C-H functionalization in general, Friedel-Crafts reactions and other alkylation and arylation reactions result in the functionalization of C-H bonds.  Metalation reactions often involve C-H activation in the formation of C-M bonds.  The numerous cross-coupling reactions functionalize C-H bonds and in Suzuki-Miyaura coupling, the activation/metalation of the C-H to form a C-B bond  is used in the development of the required organoboron reactants. Additional important C-H activation/metalation reactions include C-Li bond formation in lithiation reactions. 

When considering catalytic reactions, there are a multitude of variables that can affect the intended outcome.  Dependent on the catalytic metal, ligands, reagents and reactants used, the temperature, pressure, mixing, dosing rates are all critical to the outcome.  As a result, investigating the kinetics, mechanism and thermodynamics of catalytic reactions is actively pursued as is postulating the catalytic cycle. To accomplish this requires careful control of reaction variables and the capability for tracking key species under actual reaction conditions. 

Chemical syntheses employing C-H bond activation represent one of the most prolifically researched areas in chemistry.  The ever-widening scope of C-H activation reactions, and related functionalization of carbon bonds, is a direct result of in depth understanding of the kinetics, mechanism and pathways of catalytic processes.

Acquiring high quality data for these measurements requires precise and accurate control of fundamental reaction parameters/variables, including temperature, pressure, reactant dosing rate and stirring rate. EasyMax and OptiMax automated  chemical reactors are used in academic and industrial labs for this. EasyMax capability has recently been expanded to enable precise control of temperatures as low as -78 °C - even when unattended, extending the design space for C-H activation type reactions. EasyMax can be equipped with calorimetric capability (EasyMax HFCal) for measuring reaction thermodynamic properties and for safety considerations.

The assurance provided by superior reactor control facilitates confidence in the measurement accuracy of reaction species that include reagents, reactants, catalyst species, catalyst-ligands, transient intermediates and by-product impurities.  Data-rich experiments from in situ, real-time tracking of these reaction species speed the development of kinetic parameters and support for proposed reaction mechanisms including catalytic cycles.   As evidenced in the chemical literature, in situ, real-time FTIR spectroscopy and Raman spectroscopy are well-proven methods for in-depth understanding of catalytic reactions. ReactIR and ReactRaman analyzers are specifically designed for chemical reaction analysis, and feature a range of insertion probes and flow cells that handle the broad temperature and pressure range often required for C-H activation and functionalization investigations. When offline analysis by chromatography is required,  EasySampler is an automated sampling technology for in-line acquisition, quenching and dilution of reaction samples. EasySampler allows samples to be retrieved under reaction conditions, eliminating the issues associated with manual sampling of chemistry performed at challenging temperatures, pressures and/or air-sensitive reactions.

EasyMax and OptiMax automated synthesis reactors are chemistry workstations ideal for the research, development and parameter optimization of chemical reactions including C-H activation and functionalization reactions.  The chemical reactors offer precise control of virtually all reaction variables associated with C-H activation reactions, including those performed at elevated or subambient temperatures.

• Control and record all critical parameters including reagent dosing rate, temperature, mixing and pressure 
• Ideal for performing kinetics and mechanistic investigations, which are critical in the development of C-H activation syntheses
• Provide superior support for DoE studies and data-rich experiments, such as Reaction Progress Kinetics Analysis (RPKA) 
• Fully integrates in-situ, real-time spectroscopy, including ReactIR (FTIR), ReactRaman (Raman), as well as EasySampler for automated, in-situ reactor sampling when off-line analysis is required
• iC software enables automated execution and control of all experiments and peripheral equipment, as well as full data capture and record keeping

Qiang Yang, Belgin Canturk, Kaitlyn Gray, Elizabeth McCusker, Min Sheng, Fangzheng Li, “Evaluation of Potential Safety Hazards Associated with the Suzuki− Miyaura Cross-Coupling of Aryl Bromides with Vinylboron Species”,  Org. Process Res. Dev. 2018, 22, 351−359

The authors investigated safety hazards resulting from Suzuki−Miyaura cross-coupling of aryl bromides with vinylboron compounds.  Specifically, the thermal profile recorded for the cross-coupling of 1-bromo-3-(trifluoromethyl)benzene with potassium vinyltrifluoroborate under specific conditions revealed a significant exotherm upon the addition of catalytic 1,1′-bis(diphenylphosphino)ferrocene palladium(II) dichloride [Pd(dppf)Cl2].  Via calorimetric investigation with EasyMax, they determined that both the reaction rate and the exotherm were greater in aqueous systems relative to anhydrous conditions, but that even in the absence of water, the exotherm size and rate was highly dependent on reactants, reagents, solvents and catalysts.  In some cases, the maximum temperature of the reaction was greater than boiling point of the solvent or conducive to reaction mixture decomposition.

Further investigations into the specific source of the exotherm were performed.  Earlier work showed that polymerization of the styrene products can be related to exotherms.  To determine if polymerization might be the cause, ReactIR measurements were employed to track the consumption of starting material after the Pd(dppf)Cl2 was added and this was found to correlate with the observed heat conversion.  The mixture was then held under the reaction conditions for an extended period and ReactIR tracking showed no product polymerization, eliminating that potential cause.

Researchers were interested in understanding the kinetics profile, mechanism of impurity formation, and determining the endpoint for this palladium catalyzed C-H activation reaction.  They found that if oxygen is introduced to the headspace of the reactor, the reaction stalls, and oxygen levels of 5000 ppm will result in a 50 % increase in reaction time. They used an EasySampler to eliminate the possibility of accidental introduction of O₂ when sampling the reaction mixture for UPLC analysis. EasySampler is an automated inline technology for retrieving and quenching timed, representative samples from reactions, including reactions at sub-ambient or elevated temperatures, heterogeneous reactions, or air sensitive reactions.  For this reaction, EasySampler was used to capture and quench 12 samples over a 24 hour period.

The UPLC-generated reaction profile provided insight into interconnectivities of the impurities observed in the mixture, and especially highlighted the need for a tight reaction cycle time. Based on this information, researchers were able to quickly set in-process controls to relate reaction time with primary conversion and impurity levels. They determined that when the product reaches a maximum conversion at approximately 7 to 8 hours, the temperature of the reaction system needs to decrease to 20 °C to avoid the cyano impurity formation. If the mixture continues stirring too long, the Des-CN by-product forms suddenly and cannot be removed easily in subsequent workup and reaction steps.

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