Grignard Reagent Formation Research Articles

Selectivity of Grignard Reagent Formation: From Semibatch to Continuous Lab and Pilot Scale

Selectivity of Grignard Reagent Formation: From Semibatch to Continuous Lab and Pilot Scale

Synthesis of Sterically Encumbered Alkaline-Earth Metal Amides Applying the In Situ Grignard Reagent Formation.

Magnesium and calcium are too inert to deprotonate amines directly. For the synthesis of bulky amides alternative strategies are required and in the past, N-bound trialkylsilyl groups have been used to ease metalation reactions. The in situ Grignard reagent formation in stirred suspensions of magnesium or calcium with hydryl halide and imine in THF allows the synthesis of a plethora of amides with bulky silyl-free substituents. Ball milling protocols partially favor competitive side reactions such as aza-pinacol coupling reactions. Calcium is the advantageous choice for the in situ Grignard reagent formation and subsequent addition onto the imines yielding bulky calcium bis(amides) whereas the stronger reducing heavier alkaline-earth metals strontium and barium are less selective and hence, the aza-pinacol coupling reaction becomes competitive. Exemplary, the solid-state molecular structures of [(Et2 O)Mg(N(Ph)(CHPh2 )2 ] and [(Et2 O)2 Ca(N(Ph)(CHPh2 )2 ] have been determined.

Impact of residence time distributions in reacting magnesium packed beds on Grignard reagent formation – selectivity of Grignard reagent formation (part 2)

The selectivity of the benchmark benzylmagnesium bromide synthesis is influenced by the degree of backmixing and is enhanced by choosing a tubular flow reactor instead of a batch reactor and by application of a suitable pump-induced flow behavior.

Impact of residence time distributions in reacting magnesium packed beds on Grignard reagent formation – pump-induced flow behaviour in non-reacting magnesium beds (part 1)

The RTD within a randomly packed bed of non-uniform, non-spherical Mg turnings depends on the properties of the Mg turnings and the pump-induced flow behavior. Using oscillatory flow rates, Bodenstein numbers can be increased by up to 70%.

Cobalt-Catalyzed Formation of Grignard Reagents via C-O or C-S Bond Activation.

C(aryl)-OMe bond functionalization catalyzed by cobalt(II) chloride in combination with a nacnac-type ligand and magnesium as a reductant is reported. Borylation and benzoylation of aryl methoxides are demonstrated, and C(aryl)-SMe bond borylation can be achieved under similar conditions. This is the first example of achieving these transformations using cobalt catalysis. Mechanistic studies suggest that a Grignard reagent is generated as an intermediate in a rare example of a magnesiation via a C-O bond activation reaction. Indeed, an organomagnesium species could be directly observed by electrospray ionization mass spectroscopic analysis. Kinetic experiments indicate that a heterogeneous cobalt catalyst performs the C-O bond activation.

Strongly reducing magnesium(0) complexes.

A complex of a metal in its zero oxidation state can be considered a stabilized, but highly reactive, form of a single metal atom. Such complexes are common for the more noble transition metals. Although rare examples are known for electronegative late-main-group p-block metals or semimetals1-6, it is a challenge to isolate early-main-group s-block metals in their zero oxidation state7-11. This is directly related to their very low electronegativity and strong tendency to oxidize. Here we present examples of zero-oxidation-state magnesium (that is, magnesium(0)) complexes that are stabilized by superbulky, monoanionic, β-diketiminate ligands. Whereas the reactivity of an organomagnesium compound is typically defined by the nucleophilicity of its organic groups and the electrophilicity of Mg2+ cations, the Mg0 complexes reported here feature electron-rich Mg centres that are nucleophilic and strongly reducing. The latter property is exemplified by the ability to reduce Na+ to Na0. We also present a complex with a linear Mg3 core that formally could be described as a MgI-Mg0-MgI unit. Such multinuclear mixed-valence Mgn clusters are discussed as fleeting intermediates during the early stages of Grignard reagent formation. Their remarkably strong reducing power implies a rich reactivity and application as specialized reducing agents.

Electron-transfer oxidation of Organo-cuprates with Benzophenone: Synthesis of Biaryls

A mild and simple way to synthesize Biaryls from aryl bromides via formation of organo-cuprate complexes has been developed. The Organo-cuprates {Ar2CuMgBr.Mg(I)Br}, generated from Arylmagnesium bromide and half equivalent of copper(I) iodide in dry THF at lower temperature under nitrogen, underwent electron-transfer oxidation with an aryl ketone benzophenone producing homo-coupled Biaryls in moderate yields. Aryl bromides either with electron-donating or with electron-withdrawing substituents were smoothly transformed into the corresponding Biaryls through formation of aryl Grignard reagents and Organo-cuprate complexes in a one pot reaction under this electron-transfer oxidation procedure.

Effect of magnesium cluster size on Grignard reagent formation mechanism. A quantum-chemical study

The density functional theory (B3PW91/6-311[Formula: see text]G(2d,2p)) was used to obtain optimized geometry, energy and electronic properties of Mg[Formula: see text]EtBr adsorption complexes, Et[Formula: see text]Mg[Formula: see text]Br intermediates and transition states for ethyl bromide reaction with the magnesium atom and Mgn ([Formula: see text]–20) clusters modeling the distorted surface of the metallic magnesium. We suggest a consecutive multi-stage scheme of EtBr[Formula: see text]Mgn process in vacuum that includes adsorption of reagents on external cluster atoms, chemical interaction with Grignard reagent formation and desorption of products to the volume. Two fundamentally different reaction channels were investigated — the radical and molecular ones. Influence of Mgn cluster size on the preference of each of channels was established. It is shown that the reaction route is primarily determined with the position of the reactive group of atoms participating in formation of the transition state or radical intermediates and the activation energy of EtMgBr formation correlates with the energy of atom detachment from a cluster. For both pathways, reaction activation energies and thermodynamic parameters of the elementary steps were calculated.

A unified model of Grignard reagent formation

Grignard reagents are among the most fundamental reagents in organic synthesis, yet studies have hitherto failed to fully explain the selectivity and kinetics of Grignard reagent formation (GRF). The present study provides new insights into the intermediates and pathways of GRF using density functional theory (DFT) calculations. Potential energy surfaces of RX dissociation along different directions reveal the origin of configuration retention of alkenyl and aromatic halides. Radical intermediates participate solely in the dissociation stage, and depend on the geometry of the reactant halide. Dissociation of organic halides yields stabilized surface anions, and the rest of the reaction is ionic in nature. MgX+/RMg+ were proposed as the key intermediates of Mg leaving from the surface in the self-activation of GRF, which explains the accelerated kinetics upon addition of RMgX or MgX2. The intermediacy of the cations was supported by a simple electrochemical experiment. To the best of our knowledge, this is the first unified ionic model (I-model) developed for resolving the controversial issues of GRF.

Development of a Commercial Flow Barbier Process for a Pharmaceutical Intermediate

A flow Barbier process was developed to produce a key intermediate in the edivoxetine·HCl registered sequence. The control strategy was developed based on a critical understanding of integrated parameters and design space requirements for a continuous stirred tank reactor (CSTR) process. In this flow Barbier process, the Grignard reagent formation and reaction occurs in a single CSTR, with quenching of the resulting tetrahedral intermediate in a second CSTR. Real time Process Analytical Technology (PAT) monitoring was used to assist process development and understanding. The postquench liquid–liquid separation was continuous, and the quenched intermediate flowed directly into a neutralization CSTR to minimize the epimerization potential of the quenched intermediate. The optimized process was run for 80 consecutive hours in 2 L CSTRs where magnesium was recharged every 4 h for the first half of the continuous campaign and every 8 h for the second half with no quantifiable differences in performance. The Ba...

Facile Modulation of FLP Properties: A Phosphinylvinyl Grignard Reagent and Ga/P- and In/P2 -Based Frustrated Lewis Pairs.

An Al/P-based frustrated Lewis pair (FLP) reacted with PhMgCl by an unexpected transmetalation and formation of a phosphinylvinyl Grignard reagent. This compound is well suited for the transfer of the basic FLP component to other Lewis acidic metal atoms and allowed the generation of a Ga/P and an In/P2 FLP. The Ga FLP showed a behavior different to that of the corresponding Al FLP, the In FLP allowed the chelating coordination of an Au atom by Au-Cl bond activation.

ChemInform Abstract: The Influence of Main Group Metallic Lewis Acids on the Formation and Reactivity of Grignard Reagents

The significance of main group metallic Lewis acids such as LiCl, MgCl2, AlCl3 on the formation and reactivities of Grignard reagents are best demonstrated by recent quick development of their diverse synthetic techniques and versatile reactivities towards various electrophiles. Although substantial progress has been made especially on the selective formation of carbon-metal bonds employing lithium chloride as the activator, novel protocols especially these for regioselective metalation of highly functionalized substrates are continuously developed and thus occupy a hot research spot in organometallic chemistry. This mini-review provides a concise overview mainly on the behavior of main group metallic salts derived from lithium, magnesium and aluminum as a powerful tool for regioselective metalation of C-X ( X = Cl, Br, I) and C-H bonds. The diverse functions of these metallic salts on the reactivities of Grignard reagents are exemplified primarily choosing aldehyde as the electrophile.

Structural, electronic, thermodynamic and spectral properties of Mgn (n = 2–31) clusters. A DFT study

Small clusters of magnesium Mgn (n=2–31) are of particular interest for coordination chemistry and organometallic chemistry, as they are convenient models of Grignard reagent formation reaction on the surface of activated metallic magnesium, and also are directly involved in this reaction under vacuum atomized state conditions. In this study, the structure, thermodynamic functions (total energy, enthalpy and Gibbs free energy of formation of Mgn systems), and the electronic parameters (dipole moments, band-gap energy, distribution of partial atomic charges) for optimized clusters were investigated using the density functional theory (B3PW91/6-31G (d), B3PW91/6-311+G (2d)). The energies and thermodynamic functions of cluster atomization and isomerization, energies of S0→T1 singlet-triplet transitions, and energies of separation of single or multiple magnesium atoms from clusters, which are described within the framework of simple statistical models, were determined. The calculated parameters allow to estimate the properties of the clusters whose structure corresponds to different centers of magnesium surface involved in Grignard reagent formation reaction, and therefore, to estimate their contribution to reactivity. The calculated Mg2–Mg31 IR spectra enable identification of individual clusters under experimental conditions.

Many Mg-Mg bonds form the core of the Mg16Cp*8Br4K cluster anion: the key to a reassessment of the Grignard reagent (GR) formation process?

It caused a sensation eight years ago, when the first room temperature stable molecular compound with a Mg-Mg bond (LMgMgL, L = chelating ligand) containing magnesium in the oxidation state +1 was prepared. Here, we report the preparation of a [Mg16Cp*8Br4K]- cluster anion (Cp* = pentamethylcyclopentadiene) with 27 Mg-Mg bonds. It has been obtained through the reaction of KCp* with a metastable solution of MgBr in toluene. A highly-resolved Fourier transform mass spectrum (FT-MS) of this cluster anion, brought into vacuum by electrospraying its solution in THF, provides the title cluster's stoichiometry. This Mg16 cluster together with experiments on the metastable solution of MgBr show that: during the formation process of GRs (Grignard reagents) which are involved in most of sophisticated syntheses of organic products, not the highly reactive MgBr radical as often presumed, but instead the metalloid Mg16Cp*8Br4 cluster anion and its related cousins that are the operative intermediates along the pathway from Mg metal to GRs (e.g. Cp*MgBr).

The Influence of Main Group Metallic Lewis Acids on the Formation and Reactivity of Grignard Reagents

The significance of main group metallic Lewis acids such as LiCl, MgCl2, AlCl3 on the formation and reactivities of Grignard reagents are best demonstrated by recent quick development of their diverse synthetic techniques and versatile reactivities towards various electrophiles. Although substantial progress has been made especially on the selective formation of carbon-metal bonds employing lithium chloride as the activator, novel protocols especially these for regioselective metalation of highly functionalized substrates are continuously developed and thus occupy a hot research spot in organometallic chemistry. This mini-review provides a concise overview mainly on the behavior of main group metallic salts derived from lithium, magnesium and aluminum as a powerful tool for regioselective metalation of C-X (X = Cl, Br, I) and C-H bonds. The diverse functions of these metallic salts on the reactivities of Grignard reagents are exemplified primarily choosing aldehyde as the electrophile. Keywords: Grignard reagent, metallic Lewis acids, main group.

Use of 1H, 13C, and 19F-NMR Spectroscopy and Computational Modeling To Explore Chemoselectivity in the Formation of a Grignard Reagent

A discovery-based Grignard experiment for a second-year undergraduate organic chemistry course is described. The exclusive Grignard reagent formed by the reaction of 1-bromo-4-fluorobenzene (1) with Mg is 4-fluorophenylmagnesium bromide (2), which is treated with either benzophenone or CO2 to produce the corresponding fluorinated alcohol (3) or benzoic acid (4), respectively. The use of a dihalogenated Grignard reagent requires students to discern its reactivity for synthesis. Students predict the chemoselectivity of Grignard reagent formation based on the C–X bond energies of 1 and investigate their predictions by analysis of 1H, 13C, and 19F NMR, EI–MS, and IR data of 3 and 4. Empirical parameters and DFT calculations are used to predict the 1H and 13C NMR chemical shifts of 4 and the hypothetical brominated analogue.

Influence of deteriorated solvent on induction period of Grignard reagent formation

The influence of a degraded solvent on Grignard reagent formation was investigated in terms of heat release behaviour. Since degraded solvent is supposed to contain peroxide by oxidation with air as well as water from atmosphere, peroxide in this study was intentionally produced by the storage of tetrahydrofuran in a pressurized oxygen atmosphere and the induction periods were measured. The induction period which appears prior to the main exothermic reaction increased with increasing amounts of peroxide and water content, respectively. However, there was a difference in heat release behaviour; the reaction including peroxide showed a delay in the heat release and two exothermic peaks, while the solvent that included water simply showed a delay in the start of the reaction. γ-Butyrolactone was found to be a product derived from peroxide, by component analysis of the oxidized solvent. γ-Butyrolactone caused an induction period when it was added to the solvent. This work suggests a deteriorated solvent can lead to inappropriate handling which cause a runaway reaction and gives insight to the chemical industry that manages the risk of potentially hazardous chemical reactions.

ChemInform Abstract: Sequential One‐Pot Addition of Excess Aryl‐Grignard Reagents and Electrophiles to O‐Alkyl Thioformates.

The sequential addition of aromatic Grignard reagents to O-alkyl thioformates proceeded to completion within 30 s to give aryl benzylic sulfanes in good yields. This reaction may begin with the nucleophilic attack of the Grignard reagent onto the carbon atom of the O-alkyl thioformates, followed by the elimination of ROMgBr to generate aromatic thioaldehydes, which then react with a second molecule of the Grignard reagent at the sulfur atom to form arylsulfanyl benzylic Grignard reagents. To confirm the generation of aromatic thioaldehydes, the reaction between O-alkyl thioformates and phenyl Grignard reagent was carried out in the presence of cyclopentadiene. As a result, hetero-Diels-Alder adducts of the thioaldehyde and the diene were formed. The treatment of a mixture of the thioformate and phenyl Grignard reagent with iodine gave 1,2-bis(phenylsulfanyl)-1,2-diphenyl ethane as a product, which indicated the formation of arylsulfanyl benzylic Grignard reagents in the reaction mixture. When electrophiles were added to the Grignard reagents that were generated in situ, four-component coupling products, that is, O-alkyl thioformates, two molecules of Grignard reagents, and electrophiles, were obtained in moderate-to-good yields. The use of silyl chloride or allylic bromides gave the adducts within 5 min, whereas the reaction with benzylic halides required more than 30 min. The addition to carbonyl compounds was complete within 1 min and the use of lithium bromide as an additive enhanced the yields of the four-component coupling products. Finally, oxiranes and imines also participated in the coupling reaction.

Sequential One‐Pot Addition of Excess Aryl‐Grignard Reagents and Electrophiles to O‐Alkyl Thioformates

The sequential addition of aromatic Grignard reagents to O-alkyl thioformates proceeded to completion within 30 s to give aryl benzylic sulfanes in good yields. This reaction may begin with the nucleophilic attack of the Grignard reagent onto the carbon atom of the O-alkyl thioformates, followed by the elimination of ROMgBr to generate aromatic thioaldehydes, which then react with a second molecule of the Grignard reagent at the sulfur atom to form arylsulfanyl benzylic Grignard reagents. To confirm the generation of aromatic thioaldehydes, the reaction between O-alkyl thioformates and phenyl Grignard reagent was carried out in the presence of cyclopentadiene. As a result, hetero-Diels-Alder adducts of the thioaldehyde and the diene were formed. The treatment of a mixture of the thioformate and phenyl Grignard reagent with iodine gave 1,2-bis(phenylsulfanyl)-1,2-diphenyl ethane as a product, which indicated the formation of arylsulfanyl benzylic Grignard reagents in the reaction mixture. When electrophiles were added to the Grignard reagents that were generated in situ, four-component coupling products, that is, O-alkyl thioformates, two molecules of Grignard reagents, and electrophiles, were obtained in moderate-to-good yields. The use of silyl chloride or allylic bromides gave the adducts within 5 min, whereas the reaction with benzylic halides required more than 30 min. The addition to carbonyl compounds was complete within 1 min and the use of lithium bromide as an additive enhanced the yields of the four-component coupling products. Finally, oxiranes and imines also participated in the coupling reaction.

ChemInform Abstract: Practical One‐Pot Conversion of Aryl Bromides and β‐Bromostyrenes into Aromatic Nitriles and Cinnamonitriles.

AbstractThis environmentally benign one‐pot method avoids toxic metal cyanides or rare metals to prepare aromatic nitriles from aryl halides via formation of Grignard reagents and their dimethylformamide or N‐formylpiperidine adducts.