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FINE CHEMISTRY Grignard knowledge:

Alkyl coupling
chemistry with
inexpensive transition
metals
INTRODUCTION of the reaction chemistry, eventually
LARRY J. WESTRUM ascending to the highest honorary status
Boulder Scientific Company
The formation of a Grignard reagent is in chemistry - the rank of Named
Box 548 fascinating to watch. A heap of silvery Reactions.
Mead, Colorado 80542, USA magnesium turnings swirl in a clattering The formation and use of the
vortex around the bottom of a glass Grignard Reagent is a nearly universal
reaction vessel under a clear and experience among synthesis chemists.
colorless ethereal solvent. The silvery However, the range of applications has
appearance soon changes as the mixture advanced well past that described in
is treated with a clear and colorless most introductory texts, i.e., nucleophilic
organohalide (RX) in dropwise fashion. addition to carbonyl species or epoxides
Soon the clear solution becomes turbid to form alcohols or carboxylic acids. The
and the appearance of the magnesium purpose of this article is to highlight the
begins to change. Over the course of the general considerations relating to
addition of RX, the magnesium becomes Grignard technology and offer some
noticeably corroded. As the reaction interesting examples of bond-forming
begins to exotherm, the magnesium bits reactions of interest to the
begin to dance on the convection pharmaceutical community.
currents and expanding gas bubbles in
the refluxing solvent medium. As the
solvent vapor pressure rises, the reflux THE GRIGNARD REAGENT AND ITS
condenser absorbs the vapors heat PROPERTIES
burden and returns condensed solvent
back to the vessel. Over an hour or two, The Grignard Reagent is an
most of the magnesium metal has organometallic species formed by the
disappeared, indicating the reaction has formal insertion of elemental magnesium
gone to completion. What remains are (Mg0) into a carbon-halogen bond R-X
perhaps a few stray bits of magnesium (X = Cl, Br, I) (1), affording an entity
lying under a solution whose color may typically written as “RMgX”. It is generally
vary from amber to a turbid gray to the accepted that the metallation reaction
color of black tea. Neutral organic consists of a stepwise path beginning with
materials have somehow managed to a rate determining single electron transfer
digest the metallic magnesium. (SET) from metallic magnesium to the σ*
For many chemists, the generation orbital of the C-X bond of the
and use of a Grignard reagent was organohalide (2). This transfer leads to a
among the very first organic C-C bond- radical-anion/radical-cation pair at the
forming synthesis they performed as a surface of the magnesium (Figure 1).
college student. This reagent and its set Transfer of halide anion to Mg•+ to give
of bond forming reactions are ubiquitous XMg•, followed by collapse of XMg• and R•
in the synthetic literature. The year 2001 affords RMgX. The chance diffusion of R•
marked the centennial of the publication from a neighboring site can lead to dimer
by Grignard and (mentor) Barbier (R-R) formation (3). This dimer formation
describing their now famous reaction is often generalized as a “Wurtz coupling.”
mechanism. Victor Grignard went on to Though it is tempting to accept it as the
share the Nobel Prize for Chemistry with actual active species, the formula “RMgX” is
Sabatier in 1912. Throughout his career, merely a formalism that is useful in
Grignard continued to expand the scope calculating stoichiometry and proposing

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simple mechanisms. In Figure 1 - Karasch-Reinmuth-Walborsky mechanism leading to Grignard reagent complexes of the
reality, it is less than formation magnesium dihalide salt.
accurate in describing the The predominant
solvated aggregate characteristic of a
structure of the reactive Grignard Reagent is the
species (4). Fortunately for anionic aspect of the
Grignard users, large-scale carbon attached directly
industrial application occurs to the magnesium ion. It
safely and reliably without is nucleophilic and usually
detailed knowledge of the quite basic in nature.
composition of the actual These attributes -
aggregate structure. nucleophilicity and
First and foremost, the Grignard Reagent formation is usually, though basicity - while useful in bond forming
species is a metallated carbanion and not exclusively, carried out in ethereal reactions, in fact put some limits on the
shares many of the properties of other solvent systems. The presence of types of chemical moieties that can be
metallated species. It is a nucleophile and hydrocarbon co-solvents can be present during the formation and use of a
a strong base, ranking third behind tolerated to varying levels, especially at Grignard reagent.
1) RNa and 2) RLi in reactivity of the elevated temperature and pressure. A Solvents with electrophilic sites such
carbanion, based on electronegativity polarizable co-solvent like toluene can as acetonitrile, DMF, acetone, and ethyl
differences (5). Generally, the reactivity of be used in a mixed solvent preparation acetate are unsuitable owing to their great
a carbanionic reagent tends to increase ↑ of reagent. Furthermore, addition of an (and irreversible!) reactivity with RMgX.
with increasing ↑ p-character ethereal Grignard solution to a toluene Reactive moieties on the Grignard
(sp<sp2<sp3) and increasing ↑ pKa of the solution of reactant is often well substrate such as aldehydes, ketones,
conjugate acid. As a nucleophile, a tolerated in terms of solubility. An esters, amides, SO2X, nitriles, epoxides,
Grignard reagent bearing a localized (i.e., attempt to dissolve a Grignard species in hemiacetals, and most halogenated
not resonance-stabilized) carbanion will a hydrocarbon solvent will have a better moieties (i.e., Si-Cl, P-Cl, etc.), must be
generally behave as a hard nucleophile, chance for success if the Grignard protected or absent. Furthermore, the
offering higher relative reaction rates with species is solvated with an ether. presence of hetero-atom acids such as
hard electrophiles and 1,2-addition as Grignard reagents are available from water of hydration, phenols, alcohols,
opposed to conjugate addition. This commercial suppliers in drums or COOH, N-H, R3N•HCl, as well as carbon
behavior can be altered to that of a softer cylinders and are typically offered as THF acids like terminal acetylenes and
nucleophile by the addition of Cu(I) salts or diethyl ether solutions in the range of 1 enolizable groups are quite incompatible
to form a cuprate species in situ. Certain to 3 Molar. As a practical consideration, with the formation of an RMgX functional
Grignard reagents such as allylic or the reagent concentration is limited by the group on a substrate.
benzylic species may have an aptitude for solubility at temperatures the product is In general, a Grignard reagent is
conjugate or SN2’ addition without likely to encounter in transit and storage. prepared separately and combined with
transmetallation additives. Most Grignard reagents are formulated to the reaction mixture as an ethereal
Grignard reagents are strong bases remain soluble at temperatures above solution. In some cases a Grignard
and will react exothermically with a variety 20°C. The issue of solubility requires that reagent can be generated in the presence
of Lewis and Brønsted acidic species. during the cold season, Grignard reagents of the intended electrophile, which
Carbon acids such as acetylene, must be shipped in heated shipping promptly undergoes addition. This is
chloroform, methylene chloride; and containers and be stored at room referred to as a Barbier reaction or
enolizable species, and oxyacids such as temperature off the floor and on pallets. It colloquially as “Barbier conditions”.
water, alcohols, carboxylic acids; and is important for freight handlers to clearly
inorganic acids such as HX will react understand that Grignard products must
vigorously in contact with a Grignard not be allowed to sit outside and cool on SOME SYNTHETIC APPLICATIONS
reagent. An important point to consider is the loading dock or in unheated OF GRIGNARD REAGENTS
that Grignard reagents such as methyl-, temporary warehousing. The result of
ethyl-, propyl-, or butylmagnesium halides, cooling is precipitation of magnesium Although Grignard reactions trace back
when quenched with a proton, may lead salts. While this does not irreparably harm more than 100 years, the development
to the rapid formation of methane, the reagent, it does alter its composition of new reaction chemistry is far from
ethane, propane, and butane resulting in by equilibration. The original composition static. Several relatively recent and
a rapid pressure buildup in a reactor or is returned by simple dissolution of the noteworthy developments from the
storage container. Care must always be reagent by warming with agitation. literature will be discussed. But before
taken to assure that a rapid quench When a Grignard reagent solution gets proceeding with reaction specifics, some
leading to high vapor pressure products cold, solids precipitate and accumulate on basics are in order.
be avoided. the bottom of the storage container or
RMgX is very polar and consequently vessel. This elementary fact is somewhat Figure 2 - The Schlenk equilibrium
requires a coordinating solvent to keep it complicated by the Schlenk equilibrium
in solution. Ethers are most suitable owing (Figure 2). This equilibrium describes a
to the availability of lone-pair electrons for disproportionation property of RMgX
coordination to the magnesium ion and wherein factors that diminish solubility
resulting solubilization in organic media. (i.e., lowered solvent polarity or low
Examples of common solvents include temperature) result in precipitation of the
diethyl ether (Et2O), diisopropyl ether, inorganic salt MgX2 from the organic
dibutyl ether, tetrahydrofuran (THF), and solvent medium, thus driving the
butyldiglyme. Dimethoxyethane (DME) equilibrium to the right. Certain ethers
and 1,4-dioxane promote precipitation of such as DME and 1,4-dioxane drive the
MgX2 salts as a result of the Schlenk equilibrium to the right by virtue of the
equilibrium (more on this later). formation of stable coordination

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Figure 3 - Alkyl halide coupling with Grignard reagents Figure 4 - Aryl chloride coupling with alkyl Grignard reagents

Organometallic Mini-Tutorial Alkyl Cross-Coupling Reactions halides and tosylates. Thus, the reaction
affords aryl-alkyl and alkyl-alkyl products
It is worth a reminder that the Grignard reagents can be made to (Figure 3).
Grignard reagent is an electron rich undergo several types of transition The authors propose a mechanism
species. Consequently it is capable of metal catalyzed coupling reactions. wherein the Ni(II) is first reduced to
reducing some transition metal Until recently, catalyzed alkyl coupling Ni(0) by excess Grignard and then
species to a lesser positive charge, a was generally unavailable owing to reacts with 2 equivalents of
neutral state, or even negative charge. β-elimination or sluggish reactivity. 1,3-butadiene to form the coupled
Some catalytic cycles depend on an in However, several recent reports in bis-η3-octadienylnickel(II) complex 1.
situ reduction of the transition metal the literature describe Grignard- This complex undergoes nucleophilic
in the process. Grignard reagents can related systems that not only perform addition of the Grignard reagent
transfer the R anion group of RMgX alkyl couplings, but do it with affording the anionic η1,η3-complex 2,
from the magnesium to catalyst M to inexpensive iron and nickel catalysts which then undergoes oxidative
afford a transient R-M(-) species. What or with stoichiometric cuprates. addition of an alkyl halide to give
happens next depends on the metal, Obviously, iron, nickel, and copper intermediate complex 3. Reductive
its oxidation state, and what is are inexpensive and not subject to elimination affords R’-R as the system
attached to it. In the case of coupling erratic market price fluctuations that cycles back to complex 1.
reactions, the transition metal may plague buyers of the platinum group The table in Figure 3 highlights the
undergo oxidative addition to form metals. Additionally, the diverse diverse connections made possible by
R-M-R’ as a result of treatment with connectivity and selective functional this reaction. Primary alkyl bromides,
R’X. At this stage the R and R’ groups group transformations allowed by chlorides, and tosylates are coupled
are in close proximity and may form a alkyl coupling reactions offers with alkyl and aryl Grignards cleanly and
carbon-carbon σ-bond and leave the increased flexibility in the design of in high yield by this system. In addition,
vicinity of the metal as R-R’ coupled convergent syntheses. This is an alkyl bromide moiety was coupled
product. Of the combined 4 electrons welcome news for the pharma selectively in the presence of an aryl
available in the R-M and R’-M scale-up chemist engaged in the bromide group of 4-(2-bromoethyl)-
σ-bonds, 2 stay with the metal and 2 eternal search for better process bromobenzene.
are used in the R-R’ bond of the economics. We will examine a few of An iron-based catalytic system for
coupled product - thus it is a reductive these reports. the coupling of alkyl Grignards to aryl
elimination from the metals Kambe and coworkers (7) have chlorides has been reported recently by
perspective. There are a great variety reported a nickel-catalyzed cross Fürstner and coworker (8). This system
of mechanisms and the order of coupling in which aryl and alkyl (Figure 4) offers considerable promise
addition of the R groups may vary with Grignard reagents were coupled in in expanding Grignard utility not only for
the system (6a). moderate to high yields with alkyl the catalytic leverage, but also for the

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extraordinary functional group tolerance treatment of a halide with magnesium reactions based on the Grignard reagent
that is evident. turnings may be very slow at the may be economically advantageous owing
The mechanism proposed by required reaction temperature of -20°C. to the low molar expense of magnesium
Fürstner invokes the generation of an Accordingly, the authors chose to and the general availability of halogenated
Fe(-II) species 4 by the addition of 4 perform a transmetallation of the aryl precursors.
equivalents of a primary Grignard to iodide with commercially available
FeCl2. This results in the reduction of isopropylmagnesium bromide to afford
Fe(II) to a formal -2 state with the the aryl Grignard. It was found that the
concomitant generation of reduction, generation of the aryl Grignard by this REFERENCES
elimination, and coupling products from method in the presence of trimethyl
1) Carbon-fluorine bonds tend to be poorly
the Grignard reducing reagent. The phosphite afforded little homocoupling.
reactive with “unactivated” magnesium sources
proposed mechanism begins with the The table in Figure 5 shows that
such as turnings
oxidative addition of ArX to electron rich esters and amides are tolerated in the 2) WALBORSKI, H.M.; TOPOLSKI, M. J. Am.
[Fe(MgX)2] resulting in the addition coupling reactions. Of particular interest is Chem. Soc. 1992, 114, 3455
complex 5 and the disproportionation the diallylaniline moiety. An olefin 3) Ashby and Oswald have offered evidence that
of the Mg moiety. This is formally a 2 functional group might be expected to approximately 25% of the Grignard reagent is
electron oxidation of Fe(-II) to Fe(0). coordinate with many platinum group formed from radicals that escape into the
The Fe(0) then undergoes an alkylation metal catalyst systems, possibly affording solvent and return to the magnesium surface to
by a Grignard coupling reagent affording an altogether different manifold of complete the reaction: see ASHBY, E.C.;
6, which upon reductive elimination of product possibilities. A transition metal OSWALD, J. J. Org. Chem. 1988, 53, 6068
the coupling product, Ar-R, regenerates species that couples in the presence of 4) SEE: SILVERMAN, G.S.; RAKITA, P.E.
Handbook of Grignard Reagents; Marcel
the [Fe(MgX)2] species. esters, amides, and olefins is a useful
Dekker: New York, 1996; ISBN:
What is striking about the Fürstner thing. However, the requirement for an 0-8247-9545-8
chemistry is the excellent selectivity. As aryl iodide precursor is somewhat of a 5) SCUDDER, P.H. Electron Flow in Organic
seen in the table in Figure 4, in the detraction from the process chemistry Chemistry; John Wiley & Sons: New York,
presence of the [Fe(MgX)2] catalyst a perspective, but, arguably, may be more 1992; ISBN 0-471-61381-9
Grignard reagent will react exclusively than offset by the functional group 6) a. See HEGEDUS, L. Transition Metals in
with the chloride moiety, leaving tolerance shown by the chemistry. Organic Synthesis; University Science
otherwise sensitive functional groups Books, California, 1994. ISBN
like esters and nitriles unchanged. In 0-935702-28;
contrast to the success of numerous In summary, a general case has been b. p.138
7) TERAO, J.; WATANABE, H.; IKUMI, A.;
examples of alkyl Grignards, butyllithium made for the continuing vitality of
KUNIYASU, H.; KAMBE, N. J. Am. Chem. Soc.
failed to couple. Although not shown in Grignard chemistry with some recent 2002, 124, 4222-4223
the table, the reaction does favor examples of unique bond forming 8) FÜRSTNER, A.; LEITNER, A. Angew. Chem.
electron deficient aryl chlorides. Electron reactions using nickel, iron, and copper Int. Ed. 2002, 41, 609-612
rich aryl substrates containing alkoxy or catalysts and additives. It is worth 9) DOHLE, W.; LINDSAY, D.M.; KNOCHEL, P. Org.
alkyl substituents were shown to couple considering that C-C bond forming Lett. 2001, 3, 2871-2873
with the corresponding tosylate or
triflate in good yield. For the scale-up Figure 5. Cu-Mediated cross-coupling of aryl iodides and alkyl iodides
chemist this selective coupling reaction
affords the potential for greater
convergence and less time spent in
protection/deprotection gymnastics in
the execution of a synthetic scheme.
A Cu(I)-mediated cross-coupling
reaction of functionalized primary alkyl
iodides with functionalized aryl cuprates
(Figure 5) has been reported by
Knochel and coworkers (9). This
chemistry is notable for the generation
and transmetallation of a Grignard in
the presence of a labile functional
group like ester. The overall strategy
involved a Grignard species in two
distinct ways. First, an aryl iodide 1
bearing a reactive Functional Group
(FG1) was metallated with
isopropylmagnesium halide at low
temperature to afford ArMgX 2. Second,
Grignard 2 serves as a precursor for
transmetallation with copper(I) for
generation of a cuprate 3 (abbreviated
as “Cu”). Cuprates are commonly
generated by transmetallation of RMgX
or RLi with Cu(I)X. Although many
applications use catalytic quantities of
Cu(I)X, the chemistry cited worked best
at stoichiometric levels of Cu (i.e., 1 eq
CuCN·LiCl).
Generation of a Grignard reagent by

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