Grignard Reagent

7 Key excerpts on "Grignard Reagent"

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  eBook - ePub

  Handbook for Chemical Process Research and Development, Second Edition

  • Wenyi Zhao(Author)
  • 2023(Publication Date)
  • CRC Press

    (Publisher)

  11 Grignard Reagent and Related Reactions

  DOI: 10.1201/9781003288411-11

  The Grignard Reagent has played a significant role in organic synthesis since its discovery in 1900 by a French chemist, Victor Grignard. The Grignard Reagent is such a diverse reagent that it can participate in a wide range of reactions, such as coupling reactions, oxidations, nucleophilic aliphatic substitutions, and eliminations. The Grignard reaction is the addition of organomagnesium halides (Grignard Reagents) to ketones or aldehydes, to form tertiary or secondary alcohols. The reaction with formaldehyde leads to primary alcohols.

  11.1 PREPARATION OF Grignard ReagentS

  In general, the Grignard Reagent can be made through reactions of alkyl or aryl halides with magnesium. Magnesium can take three basic physical forms: turnings, powder chips, and finely divided metal. Magnesium turnings are easy to handle but can cause abrasiveness to glass-lined reaction vessels if stirred for a long period of time. Powdered magnesium is more reactive but can be pyrophoric. Magnesium chips have a smaller surface area than magnesium turnings, which results in less reactivity.

  The main hazard associated with the preparation of the Grignard Reagent is the induction period because of the oxide layer on the metal surface. In addition, the reaction is sensitive to water and impurities which can result in delayed initiation periods. As the insertion of magnesium into C–X bond is an exothermic process (380 kj/mol Mg), accumulation of the halide in the presence of magnesium metal should be avoided or a runaway reaction may occur. Real-time monitoring

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  of the reaction progress by FTIR can provide valuable information including initiation and subsequent reactions.

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  Therefore, the development of safe and robust initiation methods becomes critical for large-scale production. The preparation of the Grignard Reagent from halide with magnesium metal turnings is a heterogeneous reaction and shall be performed in a flat-bottomed reactor with efficient agitation to provide a large surface area. With conical-bottomed reactor Mg turnings accumulated at the bottom valve, resulting in a slow or incomplete reaction.

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  Main Group Metals in Organic Synthesis

  • Hisashi Yamamoto, Koichiro Oshima, Hisashi Yamamoto, Koichiro Oshima(Authors)
  • 2006(Publication Date)
  • Wiley-VCH

    (Publisher)

  Grignard received the Nobel Prize for his discovery in 1912, and organomagne- sium halides are now called Grignard Reagents in his honor. 51 3 Magnesium in Organic Synthesis Atsushi Inoue and Koichiro Oshima Scheme 3.1 Scheme 3.2 After this sensational discovery, Grignard Reagents soon became the most im- portant tools of all organometallic compounds in the chemical laboratory. Numer- ous reports have been published on preparative methods, synthetic applications, chemical and physical properties, structures, the mechanism of formation, and re- actions of the reagents. Many industrial applications of Grignard Reagents have also been reported. Here we will describe the preparation of organomagnesium compounds and the synthetic application of those compounds. Recent develop- ment, specially halogen-magnesium exchange reactions and radical reactions with Grignard Reagents are main topics of this chapter. Before those topics, several im- portant reactions such as addition to carbonyl compounds, copper- or nickel-cata- lyzed coupling reactions, and deprotonation with magnesium amides will be dis- cussed briefly. 3.2 Preparation of Organomagnesium Compounds Grignard Reagents have proved to be extremely powerful synthetic tools because of their easy accessibility and high reactivity; they enable the nucleophilic introduc- tion of organic groups as carbanion equivalents and for that reason are in stan- dard repertoires for both organic and organometallic synthesis. 3.2.1 Preparation from Alkyl Halides and Mg Metal [1] By far the commonest method for preparing organomagnesium compounds re- mains the classical Grignard reaction of magnesium with organic halides, and most of those commercially available are solutions prepared in this way. Several manufacturers have facilities for preparing Grignard Reagents on a “fine chemi- cals” scale, and a surprising number are offered for sale as laboratory chemicals.

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  Experimental Organic Chemistry

  A Miniscale & Microscale Approach

  • John Gilbert, Stephen Martin(Authors)
  • 2015(Publication Date)
  • Cengage Learning EMEA

    (Publisher)

  In each of these reactions, the nucleophilic carbon atom of one reactant becomes attached to the electrophilic car-bon atom of the other reactant with the resulting formation of a new carbon-carbon bond. Thus, like many bond-forming processes, these reactions may be viewed in the simple context of combinations of Lewis bases with Lewis acids. An alkyl halide An organometallic reagent R 1 CH 2 M + X CH 2 R 2 An alkane R 1 CH 2 CH 2 R 2 + MX d + d – d + d – (19.1) An aldehyde or ketone A metal alkoxide An organometallic reagent H 3 O + R 1 CH 2 M + C O R 1 CH 2 C R 2 R 3 O – M + R 2 R 3 An alcohol R 1 CH 2 C O H R 2 R 3 d + d + d – d – (19.2) The following discussions focus on the preparation and reactions of two important classes of organometallic compounds, Grignard Reagents 1 (M 5 MgX) and organozinc reagents 1 (M 5 ZnX). Of course, many of the principles that are presented may be applied to the chemistry of other organometallic reagents. The first series of experiments encompass the preparation of Grignard Reagents from aryl and alkyl bromides, followed by their representative reactions with (1) an ester to produce a tertiary alcohol, (2) carbon dioxide to produce a carboxylic acid, and (3) an aldehyde to produce a secondary alcohol. The other set of experiments involves the preparation of an organozinc reagent and its reaction with a ketone to prepare a tertiary alcohol. 19.2 G R I G N A R D R E A G E N T S : P R E P A R A T I O N Grignard Reagents, R – MgX or Ar – MgX, are typically prepared by the reaction of an alkyl halide, R – X, or an aryl halide, Ar – X, with magnesium metal in an anhydrous ethe-real solvent (Eq. 19.3); the organometallic reagent dissolves as it is formed. You may note that carbon is transformed from an electrophilic center in the starting material R – X or Ar – X into a nucleophilic center in the product R – MgX or Ar – MgX in this process.

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  Survey of Progress in Chemistry

  Volume 1

  • Arthur F. Scott(Author)
  • 2013(Publication Date)
  • Academic Press

    (Publisher)

  The Structure of the Grignard Reagent and the Mechanisms of Its Reactions R U D O L F M. S A L I N G E R University of Cincinnati, Cincinnati, Ohio I. S t r u c t u r e of t h e G r i g n a r d R e a g e n t 301 II. M e c h a n i s m s of G r i g n a r d R e a c t i o n s 311 A . A l d e h y d e s a n d K e t o n e s 311 B . E s t e r s 317 C. A l k y n e s 317 D . N i t r i l e s 319 E . I m i n e s 320 F . S u m m a r y 320 R e f e r e n c e s 323 I. Structure of the Grignard R e a g e n t In 1899 Barbier found that ketones react with alkyl halides in the presence of magnesium metal to give, after hydrolysis, alcohols: RCOCH3 + CH3I + M g -* R C ( 0 H ) ( C H 3 ) 2 (1) Shortly thereafter Victor Grignard (1900) discovered that this reaction can b e carried out i n two steps. The alkylmagnesium halide is prepared i n ether solution, CH3I + M g -> C H 3 M g I (2) then an aldehyde or ketone is added: R2CO + C H 3 M g I R 2 C ( C H 3 ) ( O M g I ) (3) 301 302 RUDOLF Μ. SALINGER The magnesium alcohólate upon hydrolysis yields the corresponding alcohol: R 2 C ( C H 3 ) ( O M g I ) + H 2 0 -* R 2 C ( C H 3 ) ( O H ) + J M g l 2 + J M g ( O H ) 2 (4) These organomagnesium halides, which could be individually prepared and subsequently allowed to react with carbonyl compounds, soon became popularly called Grignard Reagents, and provided a most useful syn-thetic tool for the organic chemist. This reaction was extended to aryl halides by Tissier and Grignard in 1901; reactions involving these organo-magnesium compounds were soon labeled Grignard reactions. This versatile new reagent soon aroused considerable interest concern-ing its precise structure. The designation 1 RMgX used by Grignard was a simplification, but one that could be used with appreciable success in describing and predicting the reactions of the Grignard Reagent with many substrates.

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  The Lightest Metals

  Science and Technology from Lithium to Calcium

  • Timothy P. Hanusa(Author)
  • 2015(Publication Date)
  • Wiley

    (Publisher)

  208 Furthermore, the reaction of these compounds with another metal halide leads to amorphous intermetallics or alloys.

  A very recent example of a molecular inorganic Grignard Reagent has been presented by Jones and coworkers.209 They treated a magnesium(I) complex shielded by demanding β-diketiminate ligands (see Low Oxidation State Chemistry ) with a crowded amidomanganese bromide and isolated RR′N–Mn–Mg–Nacnac (Nacnac = N,N′-disubstituted β-diketiminate), containing a high-spin manganese(0) atom (equation 27 ). The initial formation of a manganese(I) species is proposed; however, dimerization is prevented by the bulky amides. Instead, a second reduction step yields the heterobimetallic manganese–magnesium complex. This compound again represents a reducing agent and could be of similar preparative value as is the magnesium(I) species.

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  4 Conclusion and Prospective Development

  The common organomagnesium Grignard Reagents were developed into a very prominent substance class during the last century. As is appropriate to their importance and wide use as reagents in organic and organometallic chemistry, extensive studies have been conducted on their synthesis, solution behavior (e.g., Schlenk equilibrium and aggregation), physical and spectroscopic properties, and structural characteristics. During the last 20 years, additional investigations in Grignard chemistry focused on enhancements to regio- and stereoselectivity, tolerance of functional groups, stability in organic solvents, and reactivity toward diverse substrates. Calcium-based organometallics have been studied as well, as their reactivity is expected to be higher than of classic Grignard Reagents owing to the larger heteropolar character of the metal–carbon bonds (e.g., quantum chemical calculation of ionicity of the Ae–C bonding in AeMe2 : Mg, 77; Ca, 89; Sr, 91; Ba, 94%).210 In addition, calcium-mediated polymerization reactions and homogenous catalysis86, 87, 211 (see Magnesium and Calcium Complexes in Homogeneous Catalysis ) are attractive research areas because calcium is both globally available and nontoxic, and hence, its application in medicinal and biochemical fields is extremely appealing. Thus, for example, calcium-mediated polymerization of lactide represents an intensively studied research area.212 The recent advances in organocalcium chemistry and the straightforward synthesis of organocalcium complexes have promoted this field of Grignard-type reagents, one that has been characterized as “Calcium's Awakening”.213

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  Organic Chemistry, Student Study Guide and Solutions Manual

  • David R. Klein(Author)
  • 2017(Publication Date)
  • Wiley

    (Publisher)

  After the reaction is complete, an aqueous workup then gives the desired product. (b) In this case, a third equivalent of the Grignard Reagent is required because of the presence of the alcohol functional group. The acidic proton of the alcohol will react with one equivalent of the Grignard Reagent. (c) In the first step of the mechanism, a proton-transfer reaction occurs. One equivalent of the Grignard Reagent (methyl magnesium bromide) functions as a base and removes the proton of the alcohol. This step requires two curved arrows. In the second step of the mechanism, a second equivalent of the Grignard Reagent functions as a nucleophile and attacks the C=O bond of the ester. This step requires two curved arrows. The resulting intermediate then ejects a leaving group to give a ketone, which also requires two curved arrows. The ketone is then further attacked by a third equivalent of the Grignard Reagent. Once again, two curved arrows are used to show the nucleophilic attack, resulting in a dianion. Finally, the dianion is then protonated upon treatment with water. There are two locations that are protonated, each of which requires two curved arrows, as shown. Notice that each anion is protonated in a separate step (this should not be drawn as one step with four curved arrows, because there are two distinct processes occurring, and it is unlikely that they occur precisely at the same moment). 12.16. (a) This type of transformation can be achieved via a Grignard reaction. However, the starting material has an OH group, which is incompatible with a Grignard reaction. To resolve this issue, we must first protect the OH group and then perform the desired Grignard reaction. Deprotection then gives the desired product, as shown. 406 CHAPTER 12 (b) This type of transformation can be achieved via a Grignard reaction in which the Grignard Reagent is treated with 0.5 equivalents of an ester.

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  Organic Reaction Mechanisms 1979 (Including Index 1975-1975)

  An annual survey covering the literature dated December 1978 through November 1979

  • A. C. Knipe, W. E. Watts, A. C. Knipe, W. E. Watts(Authors)
  • 2008(Publication Date)
  • Wiley

    (Publisher)

  111 2-Phenyl-3H-indol-3-one reacts with Grignard Reagents to give a mixture of 2,3-dihydro-2-alkyl(or phenyl)-2-phenylindoI-3-ones (ionic mechanism) and 2- phenyl-3-alkyl(or phenyl)-3H-indol-3-oIs (single-electron-transfer mechanism) ; the product ratios obtained were dependent on the Grignard Reagent used and, to a small extent, on the reaction medium.112 In the presence of benzyne, allylic Grignard Reagents undergo three competitive reactions : nucleophilic addition, and (712+712)- and (~4+n4)-cycloadditions ; with cyclohexyne only nucleophilic addition is observed.113 Both lithium and Grignard Reagents (RM) react in an unprecedented manner with oxaziridines to afford coupling and hydroxylation products; a mechanism which explains the hydroxylation of RM by oxaziridine (51) is outlined in Scheme 2.114 In the cross-coupling reaction between phenyl halides and sec- R = Ph, Bun, or octyl M = Li or MgBr SCHEME 2 (51) 10 Carbanions and Electrophilic Aliphatic Substitution 365 butylmagnesium halides carried out in the presence of [( +)(~)-1,2-bis(diphenyl- phosphino)propane]nickel(~~) chloride, the absolute configuration of the derived 2-phenylbutane can be reversed by changing the halogen of the Grignard Reagent: the (s)-enantiomer is prevailingly formed when starting with BusMgC1, whereas the (R)-enantiomer predominates when BuSMgBr or BuSMgI is used.115 Iodination of y-functionally substituted vinylic Grignard Reagents, prepared by stereospecific addition of organomagnesium compounds to cr-acetylenic or y-allenic alcohols, affords vinyl iodides, which can be converted into allylic alcohols with high stereo- selectivity by treatment with Grignard Reagents in the presence of (PPh,),NiCI,.I 16 These vinylic Grignard Reagents also provide access to A.

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