Grignard Reaction Mechanisms

In a Grignard reaction, alkyl-, aryl-, vinyl organomagnesium halide compounds react with molecules that have polarized bonds, including ketones, esters, aldehydes, organic acids, nitriles, and amides. These organomagnesium halide compounds, known as Grignard reagents, are nucleophiles that attack the electrophilic carbon atom in, for example, carbonyl bonds. Grignard reactions are important due to their ability to form carbon-carbon bonds.

Grignard reagents are strong bases and will react with protic compounds which makes them exceedingly valuable tools for organic synthesis. As an example, organomagnesium halides will undergo addition to the carbonyl bond of a ketone or aldehyde forming an adduct which is then hydrolyzed to form an alcohol. Hundreds of different alcohols have been synthesized via the Grignard reaction. 

The value of the Grignard reaction cannot be overstated. In general, Grignard reactions represent one of the best ways in organic chemistry to produce C-C bonds and enable the coupling of alkyl chains. For example, Grignard reagents are frequently used to alkylate aldehydes and ketones. There are few reagents available to the chemist that are as effective as Grignards for C-C bond formation.

Carbon is more electronegative than magnesium, and the metal-carbon bond in Grignard regents is quite ionic. These carbanions are quite nucleophilic and readily react with electrophilic groups such as carbonyl moieties. Thus, Grignard reagents react with formaldehyde to form primary alcohols, with aldehydes to form secondary alcohols and ketones, and esters and acid halides to form tertiary alcohols.

Reactions of various organic compounds with Grignard reagents yield amines, ketones, nitriles, thiols, aldehydes, etc. Grignard reagents can react with a variety of halides to form carbon-hetero atom bonds.

Due to the exothermicity of Grignard formation, as well overall reactivity of Grignard reagents, synthesizing them can be particularly hazardous. Notwithstanding, the formation of Grignard reagents and subsequent Grignard reactions are widely used in the production of fine chemical and pharmaceutical compounds.

The synthesis of a Grignard reagent may have a variable induction period associated with an autocatalytic process that accelerates the formation of radicals on the magnesium metal. Although the reaction may be slow to initiate, as the number of magnesium radicals quickly increase, the reaction may advance rapidly with concurrent significant heat release. If not well controlled, this issue of induction period followed by rapid initiation may result in a runaway reaction. The variability and overly-lengthy induction period is often due to the presence of trace impurities in solution, or passivity caused by an oxide layer on the magnesium surface. Overdosing the organohalide during this period exacerbates the hazardous nature of the reaction when initiation occurs.

The issues associated with reagent and reactant purity, the type of Grignard reagent formed, and reaction variables need to be carefully understood and controlled. For this reason, chemists and engineers have turned to the RC1mx reaction calorimeter to measure the exothermicity of Grignard reactions, and ReactIR to monitor the organic halide concentration dosing and to track the formation of the Grignard reagent.  The use of heat and mass balance online monitoring reveals the link between reaction variables and reaction performance, ensuring the safety of Grignard reagent synthesis.

The pharmaceutical industry increasingly embraces continuous flow chemistry either as an alternative or in conjunction with traditional batch syntheses. The advantages of flow chemistry are well understood. Among the most important advantages are reducing the hazards of reactions, since only small amounts of energetic materials are either formed or used at any given time. Also, due to the high surface area of flow apparatus, superior control of temperature and in particular exotherms, is enabled. For these reasons, the use of flow chemistry in the synthesis of Grignard reagents, and the application of these reagents to a wide range of organic syntheses, is greatly expanding. Inline FTIR spectroscopy via ReactIR equipped with an optimized FTIR-ATR flow cell is frequently used in flow syntheses to monitor the formation of the Grignard reagent and/or the final product of the Grignard reactions.

As an example, a recent article described the redesign of process for an API that used a continuous flow strategy, which provided numerous advantages over the existing batch process. The advantages included fewer synthetic steps, lower energy consumption and less raw material usage. One of the key steps was developing a continuous flow method for the initial step, a Grignard addition between between 10,10-dimethylanthrone (10,10DMA) and 3-(N,N-dimethylamino)propylmagnesium chloride, resulting in formation of the magnesium alkoxide. A ReactIR flow cell was placed inline after the first reactor coil to monitor the Grignard step in the overall reaction sequence, specifically tracking the carbonyl group of the 10,10DMA starting material as a function of time to ensure that complete conversion occurred.

Pedersen, M., Skovby, T., Mealy, M., Dam-Johansen, K., Kiil, S., “Redesign of a Grignard-Based Active Pharmaceutical Ingredient (API) Batch Synthesis to a Flow Process for the Preparation of Melitracen HCl”, Org. Process Res. Dev. 2018, 22, 228−235. DOI:10.1021/acs.oprd.7b00368 

FTIR Spectrometers

• Real-time tracking of Grignard reaction progress; follow reactants, reagents, intermediates, products, and by-products
• Safer preparation of Grignard reagents; track initiation, conversion, accumulation, stalling, endpoint
• Obtain key kinetic and mechanistic information
• Real-time monitoring of Grignard reagent synthesis and Grignards reactions in continuous flow processes

Chemical Synthesis Reactors and Reaction Calorimetry

• Precise, automated control to test and optimize reaction parameters
• Measure heat flow during Grignard reagent generation and Grignard reaction to ensure safety and optimized reaction performance
• Support development and safe scale-up efforts

• Track in situ conversion of organohalide reactant and formation of Grignard reagent
• Monitor and control accumulation of unreacted organohalide to minimize stalling and runaway reaction
• Eliminate grab sampling; measure reaction species in situ to minimize the introduction of detrimental air and moisture
• Develop real-time trending profiles for key reaction species: reactants, intermediates, products, byproducts in Grignard reactions
• Obtain data-rich information for traditional kinetic analysis or Reaction Progress Kinetics Analysis (RPKA) methods
• Test the effects of reaction variables on performance

In a typical Grignard reagent synthesis, the reactor is first charged with Mg metal turnings in THF. A small portion of the organic halide (R-X) is added and the mixture is brought to reflux. The formation of Grignard reagent can be slow to initiate but once the reaction commences, as indicated by a by exothermic temperature rise, the remaining R-X is added.

Since detection of the exotherm may be difficult under reflux conditions, in situ FTIR spectroscopy is used to monitor the organic halide concentration and the formation of the Grignard reagent. The point of reaction initiation, and the subsequent formation of the Grignard reagent, are continuously measured over the course of the reaction.

The relative R-MgBr concentration trend shows two initial additions of the aryl halide. The initiation doesn't occur until two hours into the reaction and the continuous real-time information provided by ReactIR ensures that there is a manageable accumulation of aryl halide. 

• Accumulation of reactants or energy that is clearly understood for data-driven decisions at scale
• Ensure sufficient cooling at large scale to avoid an increase of temperature followed by a runaway reaction
• Understand the impact of delayed or auto-catalyzed reactions
• Monitor pressure and gas evolutions
• Track heat and mass transfer

• Clagga, K., Holda, S., Kumarb, A., Koeniga, S., Angelauda, R., “A Telescoped Knochel-Hauser/Kumada-Corriu Coupling Strategy to Functionalized Aromatic Heterocycles”, Tetrahedron Letters, 60, (2019) 5–7.
• Gérardy, R., Emmanuel, N., Toupy, T., Kassin, V-E., Tshibalonza, N., Schmitz, M., Monbaliu, J-C., “Continuous Flow Organic Chemistry: Successes and Pitfalls at the Interface with Current Societal Challenges”, Eur. J. Org. Chem. 2018, 2301–2351.
• Hunter, S., Susanne, F., Whitten, R., Hartwig, T., Schilling, M., “Process Design Methodology for Organometallic Chemistry in Continuous Flow Systems”, Tetrahedron, 74, (2018), 3176-3182.
• Pedersen, M., Skovby, T., Mealy, M., Dam-Johansen, K., Kiil, S., “Redesign of a Grignard-Based Active Pharmaceutical Ingredient (API) Batch Synthesis to a Flow Process for the Preparation of Melitracen HCl”, Org. Process Res. Dev. 2018, 22, 228−235.
• Duan, S., Place, D., Perfect, H., Ide, N., Maloney, M., Sutherland, K., Wiglesworth, K., Wang, K., Olivier, M., Kong, F., Leeman, K., Blunt, J., Draper, J., McAuliffe, M., O’Sullivan, M., Denis Lynch, D., “Palbociclib Commercial Manufacturing Process Development. Part I: Control of Regioselectivity in a Grignard-Mediated SNAr Coupling”, Org. Process Res. Dev. 2016, 20, 1191−1202.
• Zhou, G., Moment, A., Cuff, J., Schafer, W., Orella, C., Sirota, E., Gong, X., Welch, C., “ Process Development and Control with Recent New FBRM, PVM, and IR”, Org. Process Res. Dev., 2015, 19 (1), pp 227–235.
• Brodmann, T., Koos, P., Metzger, A., Knochel, P., Ley, S., “Continuous Preparation of Arylmagnesium Reagents in Flow with Inline IR Monitoring”, Org. Process Res. Dev., 2012, 16 (5), pp 1102–1113.
• Kryk, H., Hessel, G., Schmitt, W., “Improvement of Process Safety and Efficiency of Grignard Reactions by Real-Time Monitoring”, Org. Process Res. Dev., 2007, 11, pp 1135-1140.

Investigating Grignard reagent synthesis by IR monitoring and reaction calorimetry yields significant insight into safe preparation of these important reagents. In one of the earliest examples, David am Ende and his colleagues at Pfizer demonstrated the value of these techniques for mitigating the hazards of scaling up Grignard reagent synthesis.

Initiation is the key stage which needs to be carefully monitored in order to prevent a buildup of excess organic halide, and reduce the chance of a runaway reaction. In a production scale reactor this can be difficult to ascertain. To model this, a ReactIR probe inserted into a RC-1 reaction calorimeter was used to track specific peaks in the IR spectrum associated with the aryl-halide reactant and the Grignard reagent, respectively. Reaction initiation was shown to occur when the IR peak for the aryl-halide reactant diminished and the peak associated with the Grignard reagent increased. For this particular chemistry, a well-controlled reaction resulted from adding 5 % of the total aryl-halide charge, waiting for initiation to occur, as evidenced by the IR data, and then adding the rest of the aryl-halide. The aryl-halide concentration was continually tracked after the reaction proceeded to minimize the chance of reaction upsets, such as stalling.

Concurrent with the IR monitoring, the heat flow calorimetry of the Grignard reagent formation was monitored. After the magnesium turnings in THF was brought to reflux, the 5 % charge of aryl-halide was added over a 3 minute period. The heat liberated was -89 kcal/mol of the aryl halide with a maximum heat flow of 45 W or 140 W/L removed by the reflux condenser. Once initiation commenced, the rest of the aryl-halide was added over a 1 hour period and the heat liberated was -87 kcal/mole of magnesium. The total temperature rise was calculated to be 167°C. A second experiment was carried out with constant dosing over a hour period and not waiting for initiation. In this case, the heat flow from initiation was a very high 550 W/L.

The RC1 reaction calorimetry data demonstrated the importance of careful dosing and monitoring of the aryl halide with respect to heat liberated and overall hazard reduction. This work demonstrates the importance and capability of in situ FTIR to track in real-time the accumulation of the aryl-halide before initiation, the onset of intiation, and then as a means to monitor the aryl-halide concentration after initiation.

Preparation of Grignard Reagents: FTIR and Calorimetric Investigation for Safe Scale-Up, David J. am Ende,1 Pamela J. Clifford, David M. DeAntonis, Charles SantaMaria, and Steven J. Brenek, Pfizer, Inc., Central Research, Process Research and Development, Eastern Point Road, Groton, U.S.A. Organic Process Research & Development 1999, 3, 319-329. doi 10.1021/op9901801

This research is focused on the development of an optimized route for an aromatic nucleophilic substitution reaction, coupling aminopyridine (3) and chloropyrimidine (7). The product of the reaction is an important intermediate compound in the overall synthesis of the drug Palbociclib.

The research investigated different approaches to coupling the two reagents, and route-dependent mechanisms were postulated. The development of a clinical manufacturing route involved coupling by a strong base, LiHMDS. Though yields were acceptable, the requirement for 2+ equivalents of the aminopyridine intermediate was not ideal. Furthermore, one significant impurity was formed by this reaction, which was found to be a dimer of the product molecule. Coupling with a Grignard base, i-PrMgCl, resulted in good yield without the formation of the dimer.

In situ FTIR measurements provided insight into the kinetics and mechanism of both the LiHMDS and i-PrMgCl (Grignard) coupling reactions. Also, ReactIR measurements in the LiHMDS coupling reaction revealed the formation of an imino intermediate , which was postulated to undergo internal rearrangement, forming the product molecule. This imino compound was not observed by in situ FTIR for the Grignard coupling reaction.

Duan, S., Place,D.,Perfect, H., Ide, N., Maloney, M., Sutherland, K., Price, Wiglesworth, K., Wang, K., Olivier, M., Kong, F., Leeman, K., Blunt, J., Draper, J., McAuliffe, M., O’Sullivan, M., Lynch, D., “Palbociclib Commercial Manufacturing Process Development. Part I: Control of Regioselectivity in a Grignard-Mediated SNAr Coupling”, Org. Process Res. Dev. 2016, 20, 1191−1202. https://pubs.acs.org/doi/10.1021/acs.oprd.6b00070