Introducing deep eutectic solvents to polar organometallic chemistry: Chemoselective addition of organolithium and grignard reagents to ketones in air

Article abstract of DOI:10.1002/anie.201400889

Despite their enormous synthetic relevance, the use of polar organolithium and Grignard reagents is greatly limited by their requirements of low temperatures in order to control their reactivity as well as the need of dry organic solvents and inert atmosphere protocols to avoid their fast decomposition. Breaking new ground on the applications of these commodity organometallics in synthesis under more environmentally friendly conditions, this work introduces deep eutetic solvents (DESs) as a green alternative media to carry out chemoselective additions of ketones in air at room temperature. Comparing their reactivities in DES with those observed in pure water suggest that a kinetic activation of the alkylating reagents is taking place, favoring nucleophilic addition over the competitive hydrolysis, which can be rationalized through formation of halide-rich magnesiate or lithiate species. Turning lithium green: A new protocol for the selective addition of Grignard and organolithium reagents to ketones in green, biorenewable, and deep eutectic solvents (DESs) is reported. The protocol establishes a bridge between main-group organometallic compounds and green solvents (ChCl=choline chloride; see picture). The DESs are superior reaction media for highly polar organometallic compounds.

Full text of DOI:10.1002/anie.201400889

Angewandte
Chemie
DOI: 10.1002/anie.201400889
Green Chemistry
Introducing Deep Eutetic Solvents to Polar Organometallic Chemistry:
Chemoselective Addition of Organolithium and Grignard Reagents to
Ketones in Air**
Cristian Vidal, Joaquꢀn Garcꢀa-ꢁlvarez,* Alberto Hernꢂn-Gꢃmez, Alan R. Kennedy, and
Eva Hevia*
Dedicated to Professor Bill Clegg on the occasion of his 65th birthday
Abstract: Despite their enormous synthetic relevance, the use
of polar organolithium and Grignard reagents is greatly limited
by their requirements of low temperatures in order to control
their reactivity as well as the need of dry organic solvents and
inert atmosphere protocols to avoid their fast decomposition.
Breaking new ground on the applications of these commodity
organometallics in synthesis under more environmentally
friendly conditions, this work introduces deep eutetic solvents
(DESs) as a green alternative media to carry out chemo-
selective additions of ketones in air at room temperature.
Comparing their reactivities in DES with those observed in
pure water suggest that a kinetic activation of the alkylating
reagents is taking place, favoring nucleophilic addition over the
competitive hydrolysis, which can be rationalized through
formation of halide-rich magnesiate or lithiate species.
allowing access to tertiary alcohols.[2] However, the chemo-
selectivity of these processes can be seriously compromised
by formation of undesired reduction and/or enolization
products, resulting from competing b-hydride elimination
and deprotonation reactions, respectively.[3] Modern synthetic
alternatives to overcome these unwanted side reactions
include the use of inorganic salt additives (such as CeCl3,
FeCl2, or ZnCl2),[4] as well as the in situ generation of
magnesiate (LiMgR3) complexes by mixing Grignard
reagents with alkyllithiums.[5] Aiming to boost the nucleophi-
licity of these organometallic reagents, as well as activating
the carbonyl substrates, most such approaches still require the
restriction of low temperatures (ranging from 0 to À788C) to
allow chemoselective control of the reaction. Furthermore,
the use of dry ethereal solvents and inert atmosphere
protocols is mandatory to avoid fast degradation of these
polar reagents, which can react violently with air or moisture.
These experimental constraints can greatly hamper their
synthetic usefulness in scale-up industrial processes. Thus
development of novel synthetic methodologies to use these
reagents under green conditions,[6,7] compatible with the
presence of water and air, without having a detrimental effect
in performance is the monumental challenge in polar
organometallic chemistry.
G
rignard and organolithium reagents are exceptionally
valuable organometallic reagents in synthesis. Boasting
extremely high reactivities, primarily because of the high
À
polarity of their metal carbon bonds, these reagents are
indispensable to any laboratory where synthetic chemistry is
carried out.[1] Amongst their numerous applications, their
addition reactions to ketones is one of the most versatile and
À
fundamental methodologies to generate new C C bonds
Building new bridges between traditional polar organo-
metallic synthesis and green chemistry, by pioneering the use
of Grignard and organolithium reagents in deep eutectic
solvents (DESs), herein we report remarkable progress
towards meeting this challenge which allows chemoselective
alkylation of aliphatic and aromatic ketones to be conducted
in air at room temperature and without the need of volatile
organic solvents (VOCs).
[*] C. Vidal, Dr. J. Garcꢀa-ꢁlvarez
Laboratorio de Compuestos Organometꢂlicos y Catꢂlisis
(Unidad Asociada al CSIC)
Departamento de Quꢀmica Orgꢂnica e Inorgꢂnica
Instituto Universitario de Quꢀmica Organometꢂlica
“Enrique Moles”
Facultad de Quꢀmica, Universidad de Oviedo, 33071 Oviedo (Spain)
E-mail: garciajoaquin@uniovi.es
DESs have emerged in synthesis as a new family of green
solvents which find widespread applications in a variety of
areas, spanning electrochemistry, biocatalysis, metal extrac-
tion, material chemistry, purification of biodiesel to metal-
catalyzed organic reactions.[8] DESs are mostly obtained by
mixing a quaternary ammonium salt with a hydrogen-bond
donor that can form a complex with the halide anion of the
ammonium salt. A popular choice to prepare DESs is the low-
cost and readily available ammonium salt choline chloride
(ChCl, Figure 1),[9] which in combination with biorenewable
and environmentally benign hydrogen-bond donors [that is,
glycerol (Gly), lactic acid (LA), urea or water, Figure 1] can
form an eutectic mixture.
Dr. A. Hernꢂn-Gꢃmez, Dr. A. R. Kennedy, Prof. E. Hevia
WestCHEM, Department of Pure and Applied Chemistry
University of Strathclyde, Glasgow, G1 1XL (UK)
E-mail: eva.hevia@strath.ac.uk
[**] We are indebted to MICINN of Spain (project numbers CTQ2010-
14796 and RYC-2011-08451) and the ERC. J.G.-A. thanks the
MICINN and the European ERCSocial Fund for the award of
a “Ramꢃn y Cajal” contract. We also thank the Royal Society
(University Research Fellowship to E.H.), and the European
Research Council (ERC) for the generous sponsorship of this
research. The authors thank Prof. R. E. Mulvey for insightful
discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201400889.
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temperatures are not needed to cool the reaction (but often
mandatory for ethereal solvents). Although attempts to
generate the Grignard reagent in the eutectic mixture
1ChCl/2Gly failed, isolated vinylmagnesium bromide also
reacts with the aromatic ketone 1a in the pure eutectic
mixture (without ethereal co-solvents), although the yield is
lower (60%, entry 8) than when a commercial ethereal
solution of the Grignard reagent was employed.
Figure 1. Components used in the synthesis of the DESs employed as
solvent in this work.
To start this work addition of the Grignard reagent
vinylmagnesium bromide to 2’-methoxy-acetophenone (1a)
was examined at room temperature, in air, using different
stoichiometries, (entries 1–3, Table 1) in the eutectic mixture
1ChCl/2Gly. Remarkably, the almost instantaneous formation
Encouraged by these initial findings, which glimpse the
potential that 1ChCl/2Gly and 1ChCl/2H2O have as green
solvents for the chemoselective addition of Grignard reagents
to ketones under standard bench experimental techniques, we
then assessed the scope of this methodology extending our
studies to a range of Grignard reagents with both aromatic
and aliphatic ketones (Table 2). Similarly to the experiments
Table 1: Study of the addition reaction of vinylmagnesium bromide to 2’-
methoxy-acetophenone (1a) in different deep eutectic solvents.[a]
Table 2: Addition of various Grignard reagents to ketones 1a–1c in
ChCl-based eutectic mixtures.[a]
Entry
Grignard [mmol][b]
Eutectic mixture
Yield [%][c]
Entry R1
R2
R3
DES
Yield [%] of 2[b]
1
2
3
4
1
1.5
2
2
2
2
2
2
1ChCl/2Gly
1ChCl/2Gly
1ChCl/2Gly
1ChCl/2EG
1ChCl/2H2O
1ChCl/2Urea
1ChCl/2LA
1ChCl/2Gly
20
43
78
55
57
67
30
60
1
2
3
4
5
6
o-(MeO)C6H4 Me vinyl
o-(MeO)C6H4 Me vinyl
o-(MeO)C6H4 Me Et
o-(MeO)C6H4 Me Et
Ph
Ph
1ChCl/2Gly
2a
78
1ChCl/2H2O 2a
1ChCl/2Gly 2b
1ChCl/2H2O 2b
1ChCl/2Gly 2c
1ChCl/2H2O 2c
1ChCl/2Gly 2d
1ChCl/2H2O 2d
1ChCl/2Gly 2e
1ChCl/2H2O 2e
2 f
o-(MeO)C6H4 Me ethynyl 1ChCl/2H2O 2 f
57
64
73
69
5
6[d]
7[d]
8[e]
Ph vinyl
Ph vinyl
Ph Et
Ph Et
Me vinyl
Me vinyl
44
7[c]
8[c]
9
10
11
12
Ph
Ph
24 [46]
19 [46]
79
87
77
[a] Reactions done in air at room temperature using 1 g of DES. Reaction
time 2–3 s. 1 mmol of the ketone used. [b] A commercially available 1.0m
solution of vinylmagnesium bromide in THF was used. [c] Determined by
GC and 1H NMR spectroscopy. [d] Addition of the Grignard reagent to
urea or LA was also seen. [e] Ethereal solvent removed by exhaustive
evacuation.
CH3(CH2)2
CH3(CH2)2
o-(MeO)C6H4 Me ethynyl 1ChCl/2Gly
72
[a] Reactions performed under air, at room temperature using 1 g of the
DES. Reaction time 2–3 s. 1 mmol of ketone used. Commercially
available 1.0m solutions of the relevant Grignard reagents in THF
(2 mmol) were employed. [b] Determined by GC and 1H NMR spec-
troscopy. [c] Formation of diphenylmethanol (3), resulting from the
reduction reaction was also observed, with yields displayed in brackets.
of the relevant tertiary alcohol 2a was observed in all cases,
finding a significantly improved yield of 78% when two e-
quivalents of the Grignard reagents were employed (entry 3).
Replacing Gly by other H-bond donors like ethylene glycol
(EG, entry 4) or water (entry 5) led to lower conversions. In
all cases the formation of 2a occurs chemoselectively with no
side products observed in the crude reaction mixture (only
unreacted starting material 1a). Remarkably, when the
reaction was carried out using water as a solvent, 2a was
obtained in a diminished 21% yield, indicating that the
addition reaction to 2a must be significantly slower under
these conditions than with the DES, which translates in
compiled in Table 1, the addition reactions in both eutectic
mixtures were completed in exceptionally short reaction
times (2–3 seconds), with in most cases a high degree of
selectivity, recovering only unreacted ketone. An exception
was the reaction of EtMgCl with benzophenone (1b)
(entries 7 and 8, Table 2) where the corresponding reduction
product (diphenylmethanol, 3) was also formed.[12] Consider-
ing first the two different eutectic mixtures employed,
although no direct correlation was found between the H-
bond donor component of the DESs (Gly or water) and the
outcome of the reaction, in general, better yields for the
corresponding alcohols 2 were obtained in the Gly-containing
eutectic mixture (odd entries in Table 2). Using vinylmagne-
sium bromide as an alkenylating reagent tertiary alcohols 2a,
2c, and 2e can be effectively obtained from reactions with 2’-
methoxy-acetophenone (1a) (entries 1 and 2), benzophenone
(1b) (entries 5 and 6), and aliphatic ketone 2-pentanone (1c)
a
greater degree of hydrolysis of the organometallic
reagent.[10] Interestingly, using H-donors bearing carbonyl
functionalities to generate the DES mixtures [urea (entry 6)
or lactic acid (LA, entry 7)] has a negative effect in the overall
chemoselectivity of the addition process, yielding 2a in 67 and
30% respectively, along with products generated by addition
=
of Grignard reagent to the C O bond of these H-donor
molecules.[11] Crucially the use of Schlenk techniques (N2 or
Ar atmosphere) or low temperatures (08C) is not required. In
this sense and since DESs have high heat capacities, low
2
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(entries 9 and 10), respectively. Similarly ethynylmagnesium
bromide reacts with 1a, affording 2 f in a 77 and a 72% yield
depending on the eutectic mixture employed (entries 11 and
12). Confronting the same ketone with EtMgCl, where b-
hydride transfer (reduction) is more plausible, led exclusively
to addition product 2b in 64 and 73% yields (entries 3 and 4
using 1ChCl/2Gly and 1ChCl/2H2O), although when benzo-
phenone was employed, secondary alcohol 3 was the major
product (entries 7 and 8, Table 2), while ethyl adduct 2d was
obtained in modest yields, similar to those previously
reported for the same reaction using dry THF as solvent at
08C.[4c]
Figure 2. Molecular structure of 4. Displacement ellipsoids are drawn
at the 50% probability level. Hydrogen atoms have been omitted for
clarity.
Theoretical and experimental studies monitoring the
addition reactions of carbonyl compounds by Grignard
reagents, using neat water as a solvent, have shown that
while for allyl Grignard reagents additions take place at
a comparable rate to those of the competing hydrolysis
processes,[10] alkyl analogs, such as BuMgCl, are much more
kinetically retarded (addition reaction is up to 105 times
slower),[13] and therefore protonation occurs preferentially,
yielding only trace amounts of addition products. This
behavior contrasts sharply with the reactions mentioned
above with EtMgCl and 1a where in both eutectic mixtures
(1ChCl/2Gly and 1ChCl/2H2O), the tertiary alcohol 2b is the
major product (entries 3 and 4 Table 2), hinting at some type
of kinetic activation of the Grignard reagent may be occurring
using the DESs. Furthermore in this case the conversions
observed for 2b are greater than that found when 1a is
reacted at À788C in dry THF under strictly inert atmosphere
techniques (45%). Germane to this work, Song has recently
shown that catalytic amounts of ammonium salt NBu4Cl in
THF solutions of Grignard reagents can greatly enhance the
chemoselectivity of addition reactions, minimizing formation
of enolization and reduction products.[14] The authors pro-
posed that substoichiometric amounts of the salt can shift the
position of the Schlenk equilibrium of Grignard reagents to
form dinuclear R2Mg·MgX2 species which would favor
addition. Since a main component in the eutectic mixtures
employed in this work is an ammonium salt, a related
activation effect can be operative. To explore this possibility
more, we reacted choline chloride (ChCl) with various
amounts of the Grignard reagent Me3SiCH2MgCl in THF
solvent. However, because of the poor solubility of this
ammonium salt in this organic solvent, no reaction was
observed. In contrast, the addition of one equivalent of
Grignard to the slightly more soluble NBu4Cl afforded
a solution that deposited crystals of magnesiate [{NBu4}+-
{(THF)MgCl2(CH2SiMe3)}À] (4) in a 87% yield.
of highly reactive magnesiate species as chemoselective
reagents for additions to ketones has been previously
described, but as far as we are aware, this involves the
in situ formation of a bimetallic reagent, by co-complexation
of the Grignard reagent with an organolithium.[5] These
lithium magnesiates exhibit greater kinetic reactivities and
unique selectivity profiles, unmatched by conventional mag-
nesium reagents.[15] Although the formation of a similar
compound to 4 using ammonium salt ChCl present in the
DESs employed in this work could not be demonstrated, the
possibility of the participation of more nucleophilic magnesi-
ate species in the addition reactions described in Tables 1 and
2 cannot be disregarded. This would imply that ChCl may
have a double role in these processes, as a component of the
DES mixture employed but also as part of organometallic
alkylating reagent, being a halide source.
To probe the scope of DESs in terms of the nature of the
polar organometallic reagent employed we then studied the
reactivity of ketones 1a–c with a series of organolithium
reagents (Table 3). The large increase in the polarity of the
À
metal carbon bonds in these commodity reagents when
compared with organomagnesium compounds, generally
imposes the use of much lower temperatures in order to
control their selectivity.[1] Thus, for example the addition of
BuLi to acetophenone should be performed at À788C in THF,
and even so the tertiary alcohol is obtained in a 62% yield
along with 7% yield of the unwanted aldol condensation
product.[5] Contrastingly, under the previously optimized
reaction conditions used for Grignard reagents (ChCl-based
eutectic mixtures as solvent, at room temperature in air;
Table 3), BuLi can be added instantaneously to 2-methoxy-
acetophenone (1a) to give tertiary alcohol 2g in impressive
yields (60–82%, entries 1, 2, and 3) without forming any other
by-products. We believe this makes our study unique in that it
is the first to report the successful coexistence of organo-
lithium reagents and green solvents within the same solution.
Again and as previously demonstrated for Grignard reagents,
the addition reaction of BuLi is orders of magnitude faster
than its protonation by water, ethylene glycol or glycerol
present in the DES. Showing the general applicability of this
approach, chemoselective butylation was also observed for
the exclusively aliphatic ketone 1c (entries 6 and 7 in Table 3)
in either Gly- or water-containing eutectic mixtures. Diverg-
ing from the low conversions observed in the reactions of
EtMgCl with benzophenone (1b) (entries 7 and 8 in Table 2),
X-ray crystallographic studies established that the molec-
ular structure of 4 (Figure 2) is surprisingly a monomer,
comprising a well-defined magnesiate anion, made up of a Mg
atom which binds terminally to an alkyl group, two chlorines,
and a THF molecule, and a tetrabutylamonium counterion.
1H DOSY NMR studies on solutions of 4 in [D8]THF
confirmed that this structure is retained. These results suggest
that these activating effects of the ammonium salts in THF
solutions may be best rationalized in terms of the formation of
an anionic species which should have an enhanced nucleo-
philic power over that of a neutral Grignard reagent. The use
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Table 3: Addition of organolithium (RLi) reagents to ketones 1a–1c in
Information). Although the chemical shifts observed for the
resonances for the Li-CH2 group in 1H and 13C NMR spectra
do not differ significantly to those found for LiCH2SiMe3 in
the same deuterated solvent, there is a distinct change for that
seen in 7Li NMR spectra, moving from 3.54 ppm in the
organolithium precursor to 0.61 ppm in the crystalline
product, which is consistent with a marked change in the
metal coordination sphere. Interestingly, the integration of
the ammonium butyl groups against the monosilyl group
revealed a 2:1 NBu4/CH2SiMe2 ratio which would be con-
ChCl-based eutectic mixtures.[a]
entry R1
R2
R3
DES
Yield [%] of 2[b]
1
2
3
o-(MeO)C6H4 Me Bu
o-(MeO)C6H4 Me Bu
o-(MeO)C6H4 Me Bu
1ChCl/2Gly
1ChCl/2H2O 2g
1ChCl/2EG
1ChCl/2Gly
1ChCl/2H2O 2h
1ChCl/2Gly 2i
1ChCl/2H2O 2i
1ChCl/2Gly 2j
1ChCl/2H2O 2j
1ChCl/2Gly 2k
1ChCl/2H2O 2k
1ChCl/2Gly 2l
1ChCl/2H2O 2l
2g
71[e]
82
60
75 (12)
68 (9)
73
85
80
82
81
2g
2h
4[c]
5[c]
6
Ph
Ph
Ph Bu
Ph Bu
Me Bu
Me Bu
+
sistent with forming a dianionic halolithiate [{NBu4}2 {LiCl2-
(CH2SiMe3)}2À], where two Cl anions have been transferred
to lithium. The addition of LiCl to lithium amides or
organolithium reagents has a profound effect on their
reactivity. Thus kinetic studies have shown that by adding
less than 1 mol% of LiCl to lithium diisopropylamide, its 1,4-
addition reaction to unsaturated ethers occurs 70 times
faster.[16] A similar halide-mediated accelerating effect could
also favor the addition reaction in DES over the competing
protonation process.
CH3(CH2)2
CH3(CH2)2
7
8
9
10
11
12
13
14d
o-(MeO)C6H4 Me Ph
o-(MeO)C6H4 Me Ph
Ph
Ph
Ph Ph
Ph Ph
Me Ph
Me Ph
85
72
90
84
CH3(CH2)2
CH3(CH2)2
CH3(CH2)2
Me ethynyl 1ChCl/2H2O 2m
[a] Reactions performed under air, at room temperature using 1 g of the
DES. Reaction time 2–3 s. 1 mmol of ketone used. Commercially
available 1.6m solution in hexane of BuLi and 1.8m solution in
dibutylether of PhLi (2 mmol in all cases) were employed. [b] Determined
by GC and 1H NMR spectroscopy. [c] Formation of the reduction
product 3 was also observed. [d] Lithium acetylide ethylenediamine
complex in the absence of organic solvents was employed. [e] Removing
most of the hexane under vacuum from the commercial BuLi solution
did not affect the selectivity of the addition reaction although 2g was
obtained in a slightly lower yield (66%).
In summary, this work introduces deep eutectic solvents as
superior green and biorenewable reaction media for highly
polar organometallic compounds. As illustrated with both
Grignard and organolithium reagents, these eutectic mixtures
are the solvents of choice to cross the frontiers between
synthetically useful main group chemistry and green solvents.
A comparison of the reactivity profiles of these reagents in
DES mixtures with those in pure water, suggest that a kinetic
activation of the alkylating reagents occurs in the former,
favoring nucleophilic addition over the competing hydrolysis
process. Building on recent work on the enhanced reactivity
of Grignard reagents on the addition of ammonium salts,
a plausible rationale may be the in situ formation of anionic
halide-rich magnesiate or lithiate species. Clearly, this first
crossing opens up a new, much sought after frontier of
organolithium chemistry in their practical application under
environmentally friendly conditions (green solvents, room
temperature, and in the presence of air).
the addition of BuLi to this sensitive ketone formed the
relevant tertiary alcohol 2h in much greater yields, although
small amounts of reduction product 3 could also be detected
in reaction mixtures (entries 4 and 5 in Table 3). Besides
aliphatic ones, aromatic organolithium reagents (PhLi) can
also be successfully added to both aromatic (entries 8–11 in
Table 3) and aliphatic (entries 12 and 13 in Table 3) sub-
strates.[12] Trying to push our system to its limits, the
commercially available solid lithium acetylide ethylenedi-
amine complex (without organic solvent) was added to the
reaction mixture containing the water-based DES 1ChCl/ Experimental Section
Full experimental details are included in Supporting Information.
2H2O and 2-pentanone (entry 14 in Table 3). Astonishingly,
almost quantitative (84%) formation of the desired prop-
argylic alcohol was seen, confirming that addition can be also
performed in pure eutectic mixtures. It should be noted that
the same reaction tested using H2O as a solvent gave ketone
2m in a modest 7% yield, which hints at a possible activation
effect of the organolithium reagent when it is added to the
DES mixtures.
CCDC 978224 (4) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Received: January 27, 2014
Published online: && &&, &&&&
To assess the possibility of forming a lithiate complex with
ammonium salts, similar investigations to those mentioned for
Grignard reagents were carried out. Supporting the formation
of a complex, the addition of one molar equivalent of
LiCH2SiMe3 to a NBu4Cl suspension in THF gave a solution
which on cooling deposited colorless crystals which melt very
quickly about À108C, precluding their analysis by X-ray
crystallography. Multinuclear (1H, 13C, and 7Li) magnetic
resonance investigations of this solid in [D8]THF solution
supports the formation of a new species (see the Supporting
Keywords: addition reactions · deep eutectic solvents ·
green chemistry · Grignard reagents · organolithium compounds
.
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Chemie
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eutectic mixtures cannot be only a constituent of the solvent but
also participate as a reactant. For recent examples see Ref. [8].
[12] Aromatic alcohols derived from benzophenone can be separated
from the reaction media by simple addition of water to the
reaction crude, allowing their precipitation which can then be
isolated by filtration, without the need of organic solvents.
[13] T. Holm, J. Org. Chem. 2000, 65, 1188.
[7] Solvents are responsible of most of the waste generated in the
chemical industries and laboratories. D. J. C. Constable, C.
Jimꢀnez-Gonzꢁlez, R. K. Henderson, Org. Process Res. Dev.
2007, 11, 133.
[8] For selected reviews in the area see: a) A. P. Abbott, R. C.
Harris, K. Ryder, C. DꢂAgostino, L. Gladden, M. D. Mantle,
Green Chem. 2011, 13, 82; b) C. Ruß, B. Kçnig, Green Chem.
[14] H. Zong, H. Huang, J. Liu, G. Bian, L. Song, J. Org. Chem. 2012,
77, 4645.
[15] a) R. E. Mulvey, Dalton Trans. 2013, 42, 6676; b) A. Harrison-
Marchand, F. Mongin, Chem. Rev. 2013, 113, 7470.
[16] Y. Ma, A. C. Hopeker, L. Grupta, M. F. Faggin, D. B. Collum, J.
Am. Chem. Soc. 2010, 132, 1561.
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Green Chemistry
C. Vidal, J. Garcꢁa-ꢂlvarez,*
A. Hernꢃn-Gꢄmez, A. R. Kennedy,
E. Hevia*
&&&& — &&&&
Turning lithium green: A new protocol for
the selective addition of Grignard and
organolithium reagents to ketones in
green, biorenewable, and deep eutectic
solvents (DESs) is reported. The protocol
establishes a bridge between main-group
organometallic compounds and green
solvents (ChCl=choline chloride; see
picture). The DESs are superior reaction
media for highly polar organometallic
compounds.
Introducing Deep Eutetic Solvents to
Polar Organometallic Chemistry:
Chemoselective Addition of
Organolithium and Grignard Reagents to
Ketones in Air
6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!