Preparation Of Grignard Reagents Research Articles

Crush It Safely: Safety Aspects of Mechanochemical Grignard Synthesis

The Grignard reaction has been one of the most versatile workhorses for synthetic organic chemists for more than a century. Typically, the preparation of Grignard reagents and their subsequent reactions require anhydrous solvents and a protective inert atmosphere. A recent report showed that the reactions could be performed under mechanochemical conditions by ball-milling magnesium metal, an organic halide, and a small amount of an ethereal solvent together followed by the addition of an electrophile. Excellent results were reported for a broad range of substrates even when the reaction was performed under the ambient atmosphere, making the process highly appealing to a wide synthetic community. In this commentary, some safety aspects of this mechanochemical Grignard reaction are pointed out so that appropriate risk management plans can be devised to ensure its safe use.

Mechanochemical Grignard Reactions with Gaseous CO2 and Sodium Methyl Carbonate.

A one‐pot, three‐step protocol for the preparation of Grignard reagents from organobromides in a ball mill and their subsequent reactions with gaseous carbon dioxide (CO2) or sodium methyl carbonate providing aryl and alkyl carboxylic acids in up to 82 % yield is reported. Noteworthy are the short reaction times and the significantly reduced solvent amounts [2.0 equiv. for liquid assisted grinding (LAG) conditions]. Unexpectedly, aryl bromides with methoxy substituents lead to symmetric ketones as major products.

Mechanochemical Grignard Reactions with Gaseous CO2 and Sodium Methyl Carbonate**

AbstractA one‐pot, three‐step protocol for the preparation of Grignard reagents from organobromides in a ball mill and their subsequent reactions with gaseous carbon dioxide (CO2) or sodium methyl carbonate providing aryl and alkyl carboxylic acids in up to 82 % yield is reported. Noteworthy are the short reaction times and the significantly reduced solvent amounts [2.0 equiv. for liquid assisted grinding (LAG) conditions]. Unexpectedly, aryl bromides with methoxy substituents lead to symmetric ketones as major products.

Exploration of Mechanochemical Activation in Solid-State Fluoro-Grignard Reactions.

Owing to the strength of the C–F bond, the ‘direct’ preparation of Grignard reagents, i.e., the interaction of elemental magnesium with an organic halide, typically in an ethereal solvent, fails for bulk magnesium and organofluorine compounds. Previously described mechanochemical methods for preparing Grignard reagents have involved ball milling powdered magnesium with organochlorines or bromines. Activation of the C–F bond through a similar route is also possible, however. For example, milling 1- and 2-fluoronaphthalene with an excess of magnesium metal for 2 h, followed by treatment with FeCl3 and additional milling, produces the corresponding binaphthalenes, albeit in low yields (ca. 20%). The yields are independent of the particular isomer involved and are also comparable to the yields from corresponding the bromonaphthalenes. These results may reflect similar charges that reside on the α-carbon in the naphthalenes, as indicated by density functional theory calculations.

Magnesium(I) Halide versus Magnesium Metal: Differences in Reaction Energy and Reactivity Monitored in Reduction Processes of P−Cl Bonds

AbstractMagnesium(I) halides (MgIX; X=Cl, Br, I), as high temperature molecules, are trapped and finally stored at −80 °C in toluene/donor solutions. These solutions provide insights into the fundamental mechanism of reduction reactions using activated magnesium metal as a prototype for every base metal. The most important example of such a reaction is the preparation of Grignard reagents (RMgX). The details of this highly complex mechanism especially of intermediates between Mg metal and MgII (RMgX) remain unknown until today. The same is true for the reaction of bulk magnesium with Group 15 halide compounds that give biradicaloid species. We investigate the reduction of P−Cl bonds with solutions of [MgIBr(NnBu3)]2 (1). The phosphanes [ClP(μ‐NTer)]2 (2) and (Me3Si)2N‐PCl2 (3), were chosen as they had successfully been reduced by Mg metal before. Furthermore, reactions of both 1 and Mg metal are compared with an MgI chelate complex L1Mg−MgL1 containing a strong Mg−Mg σ‐bond.

Magnesium(I) Halide versus Magnesium Metal: Differences in Reaction Energy and Reactivity Monitored in Reduction Processes of P-Cl Bonds.

Magnesium(I) halides (MgI X; X=Cl, Br, I), as high temperature molecules, are trapped and finally stored at -80 °C in toluene/donor solutions. These solutions provide insights into the fundamental mechanism of reduction reactions using activated magnesium metal as a prototype for every base metal. The most important example of such a reaction is the preparation of Grignard reagents (RMgX). The details of this highly complex mechanism especially of intermediates between Mg metal and MgII (RMgX) remain unknown until today. The same is true for the reaction of bulk magnesium with Group 15 halide compounds that give biradicaloid species. We investigate the reduction of P-Cl bonds with solutions of [MgI Br(Nn Bu3 )]2 (1). The phosphanes [ClP(μ-NTer)]2 (2) and (Me3 Si)2 N-PCl2 (3), were chosen as they had successfully been reduced by Mg metal before. Furthermore, reactions of both 1 and Mg metal are compared with an MgI chelate complex L1 Mg-MgL1 containing a strong Mg-Mg σ-bond.

Organic functionalization of epitaxial graphene on SiC through direct binding of transient radicals from the reaction mixture.

A common and versatile chemical approach for organic functionalization of graphene using a well known reaction mixture has been developed. Here we report the chemical binding of substituted aryl or alkyl radicals, transiently generated during the preparation of Grignard reagents, onto a graphene sample preloaded in a reaction vessel.

Preparation of Grignard reagents from magnesium metal under continuous flow conditions and on-line monitoring by NMR spectroscopy

A convenient method for the classical preparation of Grignard reagents from aryl halides and magnesium using a fluidized bed reactor under continuous flow conditions was developed. The process was combined with quenching of the Grignard reagent by CO2 as a model reaction performed using a second flow reactor. The formation and quenching of the reagent was monitored by on-line 1H NMR spectroscopy. The combination of continuous flow operation for Grignard reagents with reaction monitoring by on-line NMR spectroscopy allows one to quickly optimize the working conditions.

FeCl3 Catalyzed Barbier Homocoupling Reaction for Synthesis of Symmetric Biaryls

AbstractA series of biaryls and biheteroaryls were synthesized by the Barbier reaction of aryl bromide with magnesium powder and 1,2‐dibromoethane in the presence of FeCl3 in THF under reflux reaction condition. The catalytic system differentiates itself from other homocoupling reactions catalyzed by iron salts in that it requires neither the preliminary preparation of Grignard reagent nor the addition of an oxidant.

Synthesis, Characterization, Anti-Inflammatory and in Vitro Antimicrobial Activity of Some Novel Alkyl/Aryl Substituted Tertiary Alcohols

The synthesis of some novel alkyl/aryl substituted tertiary alcohols was accomplished in two steps. The synthetic route involves preparation of Grignard reagents by treating alkyl/aryl bromides with magnesium turnings in dry ether. Then substituted chalcones were reacted with the Grignard reagents to afford alkyl/aryl substituted tertiary alcohols 1-10. The structures of the synthesized compounds were assigned on the basis of FT-IR, 1H-NMR, 13C-NMR and mass spectroscopic data. The in vivo anti-inflammatory activity of the synthesized compounds was evaluated using the carrageenan-induced hind paw edema method and was compared with that of ibuprofen. Some of the newly synthesized compounds showed promising anti-inflammatory activity. The tertiary alcohols 1-10 were also screened for antibacterial activity against ten bacterial strains using seven Gram-positive and three Gram-negative bacteria and for antifungal activity against Aspergillus Flavus, Aspergillus Niger and Aspergillus pterus. Tertiary alcohols 1-10 were found to exhibit good to excellent antimicrobial activities compared to levofloxacin and fluconazole used as standard drugs.

Triflic Salt–Catalyzed Coupling: Iron Triflate–Catalyzed Homocoupling of Aryl Bromides in the Presence of Metallic Magnesium

In the presence of metallic magnesium, the homocoupling reaction of aryl bromides catalyzed by iron triflate was carried out readily in one pot. The catalyst was used successfully in this coupling reaction without preparation of Grignard reagent in advance. Meanwhile, the catalyst was recovered easily and reused smoothly with only a little loss of its activity.

Efficient Synthesis of Aryl Fluorides

Selective functionalization reactions of aromatic and heteroaromatic halides with carbon, oxygen, and nitrogen nucleophiles have attracted much attention in the last decades. In addition to typical metal-catalyzed coupling reactions, direct functionalization of aryl halides through the formation of Grignard reagents offer new ways for the efficient construction of biologically interesting carboand heterocycles. Recent elegant examples include the development of LiClmediated preparation of Grignard reagents by Knochel and co-workers. Inspired by their work and our interest in functionalization reactions of aryl halides, we have been fascinated in the direct synthesis of aryl fluoride compounds from aryl Grignard reagents. Although a large number of known pharmaceutical and agrochemical products contain fluorinated arenes (Scheme 1), which enhance solubility, bioavailability, and metabolic stability compared with non-fluorinated analogues, there is no convenient and general synthetic method available for their synthesis. Commonly known methods for the introduction of a fluorine atom to arenes require relatively harsh reaction conditions. Typical examples include the direct fluorination of arenes, the Balz–Schiemann reaction of aryldiazonium salts with HBF4, and the so-called Halex exchange reaction of activated aryl halides with metal fluorides. In addition, transition-metal-promoted fluorinations have been achieved through the use of electrophilic N!F reagents such as Selectfluor or N-fluoropyridinium salts. Unfortunately, in most of these reactions stoichiometric amounts of the transition metal must be used or specific directing groups on the substrate are required. Most recently, Buchwald and co-workers developed an elegant palladium-catalyzed fluorination of aryl triflates using AgF or CsF. Our initial investigations aimed at the fluorination of 4bromoanisole (1), which is a particularly challenging substrate for nucleophilic fluorination, to give 4-fluoroanisole (2 ; Table 1). In our model reaction we converted 1 into the corresponding aryl Grignard 3 mediated by LiCl, according to the procedure developed by Krasovskiy and Knochel. We Scheme 1. Selected examples of therapeutically important aryl fluoride compounds.

An insight into copper catalyzed allylation of alkyl zinc halides. Comparison of reactivity profiles for catalytic and stoichiometric alkylzinc–copper reagents

Abstract The γ-selective allylation of catalytic and stoichiometric alkylzinc–cuprates have been kinetically studied. The reactivity profiles generated by allylation reactions of n-butylzinc chloride catalyzed by CuX compounds (X = I, Br, Cl, CN, SCN) and also catalyzed by n-butylzinc–copper reagents and di n-butylzinc–copper reagents were evaluated. Reactivity profiles for allylation of stoichiometric n-butylzinc–copper reagents and di n-butylzinc–copper reagents were also prepared. All CuX compounds have been screened for the preparation of Grignard reagent derived n-butylzinc–copper reagents and di n-butylzinc–copper reagents. The evaluation of the profiles indicates that the active catalyst might be RCu(X)ZnCl and also to some degree, R2CuZnCl · ZnClX, which both could favor formation of γ-product. All data supports the reductive elimination of σ-allyl Cu (III) complex formed at vinylic terminal to give γ-allylated product with a quite slow isomerization to σ-allyl Cu (III) complex formed at allylic terminal to give α-allylated product. In the allylation mechanism of zinc cuprates, the role of counter ion, ZnCl+ has been discussed.

Alkyl halides reactions with cathodes or with magnesium. Grignard reagent studied with radical clocks. What is the step competing with the isomerisation of the intermediate radical?

AbstractIn the mechanism of reaction of Grignard reagent formation for alkyl halides (RX), it is generally assumed that the alkyl radical, formed by the electron transfer from the metal to this halide, reacts rapidly with the paramagnetic MgX• species. The previous comparisons of aryl halides reactivity toward magnesium and their reactivity toward a cathode strongly suggested that MgX• species are not, for the aryl halides, compulsory to rationalise the observed facts. The aryl radicals formed by electron transfer from the metal to the aryl halide would undergo a rapid second electron transfer to yield carbanions transformed into RMgX by reaction with MgX2. In contrast, for the alkyl halides, the reduction of the rapidly formed alkyl radicals into carbanions has seldom been discussed as a possible fate for these radicals, the main discussed fates being dimerisation, disproportionation, hydrogen abstraction from the solvent, rearrangement or coupling with MgX• radicals. Two main differences distinguish the reactivity of alkyl halides from their aryl halides counterpart. First, the radical anions of aryl halides may have a given lifetime whereas electron transfer to alkyl halides is concerted with the cleavage of the molecule. Second, the aryl radicals display far stronger oxidising properties than the alkyl radicals. The counterpart of this property is that aryl carbanions display weaker reducing properties than the alkyl ones. In this report, putting in perspective Grignard reaction and the experimental results obtained with identical radical clocks in electrochemistry, we tentatively provide an answer to the question raised in the title. The comparison of electrochemical patterns of reactivity of selected alkyl halides and the evolutions of yields in the preparation of Grignard reagent suggest a new explanation for the lower yields generally observed when alkyl iodides are the starting substrates. It involves an autocatalytic reaction where carbanionic species formed from the alkyl radicals and diffusing away from the metal surface, transfer one electron to the alkyl halide; the result would be the creation of two radicals leading to an increased amount of by‐products. If the carbanionic mechanism were to be retained for the formation of alkyl Grignard reagent one would have to admit that the magnesium surface behaves as a cathode displaying high current densities reminiscent of microelectrodes. Copyright © 2006 John Wiley & Sons, Ltd.

Iron-Catalyzed Homocoupling of Bromide Compounds

The homocoupling of bromide compounds was successfully performed in one pot by a combination of metallic magnesium and a catalytic amount of iron salts. The binary catalytic system differentiates itself from other homocoupling reactions catalyzed by iron salts in that it requires neither the in situ preparation of Grignard reagent nor the addition of a 1,2-dihalogen compound as an oxidant. Various aromatic and alkyl bromides underwent the homocoupling smoothly affording the corresponding symmetrical hydrocarbon compounds in moderate to excellent yields.

Monodisperse Aromatic Oligomers of Defined Structure and Large Size through Selective and Sequential Suzuki Palladium-Catalyzed Cross-Coupling Reactions

Several monodisperse aromatic oligomers of defined structure have been prepared through selective and sequential palladium-catalyzed cross-coupling reactions. The scope of the synthesis was evaluated in terms of (i) molecular size with materials ranging from relatively small sizes (5 and 6 aromatic rings) through to intermediate sizes (9 and 10 aromatic rings), right up to a monodisperse oligomer with 21 aromatic rings, and (ii) variety of molecular structure, with materials including benzene and thiophene core units, and peripheral substituents, including octyloxy, fluoro, and cyano to aid solubility and enhance polarity. The synthetic strategy involved the preparation of Grignard reagents and organolithium derivatives to generate arylboronic acids, which were then involved in selective Suzuki palladium-catalyzed cross-couplings to generate intermediate bromides. These intermediates were either converted into boronic acids and then used in further couplings or used directly in further couplings. The scop...

The Quest for Chiral Grignard Reagents

AbstractFor Abstract see ChemInform Abstract in Full Text.

The quest for chiral Grignard reagents.

The involvement of single electron transfer, i.e. of free radicals in the reactions of organomagnesium reagents could be detected with the aid of a chiral secondary Grignard reagent, in which the magnesium-bearing carbon atom is the sole stereogenic centre. So far, however, such reagents have not been accessible, because the standard preparation of Grignard reagents proceeds via free radicals. We review and summarize here our efforts to generate such a Grignard reagent 36 by asymmetric synthesis starting from an enantiomerically pure alpha-chloroalkyl-sulfoxide 30b using a sulfoxide/magnesium exchange reaction to give 33 followed by a carbenoid homologation reaction. Grignard reagent 36 turned out to be an ideal probe to learn about the extent to which SET is involved in reactions of organomagnesium reagents.

Preparation of Grignard Reagents: FTIR and Calorimetric Investigation for Safe Scale-Up

Preparation of Grignard reagents from organic halides and magnesium pose potential safety hazards on scale-up due to their high exothermic potential which can lead to overpressurization, discharge of contents, or explosion. One of the main challenges arises in ensuring the reaction has initiated before excessive accumulation of organic halide occurs or that the reaction does not stall and then reinitiate. Specifically, in production-scale equipment, it is sometimes difficult to ascertain whether initiation has occurred at all and whether it is safe to proceed. By using in situ infrared technology (FTIR), we have developed a method for safer scale-up of Grignard chemistry that can definitively identify that initiation has occurred. The process would involve adding approximately 5% of the organic halide charge and waiting for the initiation to occur using an in situ FTIR probe. FTIR spectroscopy can be used to monitor the accumulation of the halide and reveal when initiation occurs by the resulting decrease...

Triethyl phosphate as the solvent for the preparation of Grignard reagents

The Grignard reaction successfully proceeds using a Grignard reagent prepared in triethyl phosphate.