Angewandte

Chemie

DOI: 10.1002/anie.201400889
Green Chemistry

Introducing Deep Eutectic Solvents to Polar Organometallic

Chemistry: Chemoselective Addition of Organolithium and Grignard
Reagents to Ketones in Air**
Cristian Vidal, Joaqun Garca-lvarez,* Alberto Hernn-Gmez, 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 allowing access to tertiary alcohols.[2] However, the chemo-
of polar organolithium and Grignard reagents is greatly limited selectivity of these processes can be seriously compromised
by their requirements of low temperatures in order to control by formation of undesired reduction and/or enolization
their reactivity as well as the need of dry organic solvents and products, resulting from competing b-hydride elimination
inert atmosphere protocols to avoid their fast decomposition. and deprotonation reactions, respectively.[3] Modern synthetic
Breaking new ground on the applications of these commodity alternatives to overcome these unwanted side reactions
organometallics in synthesis under more environmentally include the use of inorganic salt additives (such as CeCl3,
friendly conditions, this work introduces deep eutetic solvents FeCl2, or ZnCl2),[4] as well as the in situ generation of
(DESs) as a green alternative media to carry out chemo- magnesiate (LiMgR3) complexes by mixing Grignard
selective additions of ketones in air at room temperature. reagents with alkyllithiums.[5] Aiming to boost the nucleophi-
Comparing their reactivities in DES with those observed in licity of these organometallic reagents, as well as activating
pure water suggest that a kinetic activation of the alkylating the carbonyl substrates, most such approaches still require the
reagents is taking place, favoring nucleophilic addition over the restriction of low temperatures (ranging from 0 to 78 8C) to
competitive hydrolysis, which can be rationalized through allow chemoselective control of the reaction. Furthermore,
formation of halide-rich magnesiate or lithiate species. the use of dry ethereal solvents and inert atmosphere
protocols is mandatory to avoid fast degradation of these
Grignard and organolithium reagents are exceptionally polar reagents, which can react violently with air or moisture.
valuable organometallic reagents in synthesis. Boasting These experimental constraints can greatly hamper their
extremely high reactivities, primarily because of the high synthetic usefulness in scale-up industrial processes. Thus
polarity of their metal carbon bonds, these reagents are development of novel synthetic methodologies to use these
indispensable to any laboratory where synthetic chemistry is reagents under green conditions,[6, 7] compatible with the
carried out.[1] Amongst their numerous applications, their presence of water and air, without having a detrimental effect
addition reactions to ketones is one of the most versatile and in performance is the monumental challenge in polar
fundamental methodologies to generate new C C bonds organometallic chemistry.
Building new bridges between traditional polar organo-
[*] C. Vidal, Dr. J. Garca-lvarez metallic synthesis and green chemistry, by pioneering the use
Laboratorio de Compuestos Organometlicos y Catlisis of Grignard and organolithium reagents in deep eutectic
(Unidad Asociada al CSIC) solvents (DESs), herein we report remarkable progress
Departamento de Qumica Orgnica e Inorgnica towards meeting this challenge which allows chemoselective
Instituto Universitario de Qumica Organometlica alkylation of aliphatic and aromatic ketones to be conducted
“Enrique Moles”
in air at room temperature and without the need of volatile
Facultad de Qumica, Universidad de Oviedo, 33071 Oviedo (Spain)
E-mail: garciajoaquin@uniovi.es organic solvents (VOCs).
Dr. A. Hernn-Gmez, Dr. A. R. Kennedy, Prof. E. Hevia DESs have emerged in synthesis as a new family of green
WestCHEM, Department of Pure and Applied Chemistry solvents which find widespread applications in a variety of
University of Strathclyde, Glasgow, G1 1XL (UK) areas, spanning electrochemistry, biocatalysis, metal extrac-
E-mail: eva.hevia@strath.ac.uk tion, material chemistry, purification of biodiesel to metal-
[**] We are indebted to MICINN of Spain (project numbers CTQ2010- catalyzed organic reactions.[8] DESs are mostly obtained by
14796 and RYC-2011-08451) and the ERC. J.G.-A. thanks the mixing a quaternary ammonium salt with a hydrogen-bond
MICINN and the European ERCSocial Fund for the award of donor that can form a complex with the halide anion of the
a “Ramn y Cajal” contract. We also thank the Royal Society
ammonium salt. A popular choice to prepare DESs is the low-
(University Research Fellowship to E.H.), and the European
Research Council (ERC) for the generous sponsorship of this cost and readily available ammonium salt choline chloride
research. The authors thank Prof. R. E. Mulvey for insightful (ChCl, Figure 1),[9] which in combination with biorenewable
discussions. and environmentally benign hydrogen-bond donors [that is,
Supporting information for this article is available on the WWW glycerol (Gly), lactic acid (LA), urea or water, Figure 1] can
under http://dx.doi.org/10.1002/anie.201400889. form an eutectic mixture.

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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 1 a in the pure eutectic
Figure 1. Components used in the synthesis of the DESs employed as
solvent in this work. 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.
To start this work addition of the Grignard reagent Encouraged by these initial findings, which glimpse the
vinylmagnesium bromide to 2’-methoxy-acetophenone (1 a) potential that 1ChCl/2Gly and 1ChCl/2H2O have as green
was examined at room temperature, in air, using different solvents for the chemoselective addition of Grignard reagents
stoichiometries, (entries 1–3, Table 1) in the eutectic mixture to ketones under standard bench experimental techniques, we
1ChCl/2Gly. Remarkably, the almost instantaneous formation 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 (1 a) in different deep eutectic solvents.[a]
Table 2: Addition of various Grignard reagents to ketones 1 a–1 c in
ChCl-based eutectic mixtures.[a]

Entry Grignard [mmol][b] Eutectic mixture Yield [%][c]

1 1 1ChCl/2Gly 20 Entry R1 R2 R3 DES Yield [%] of 2[b]
2 1.5 1ChCl/2Gly 43 1 o-(MeO)C6H4 Me vinyl 1ChCl/2Gly 2a 78
3 2 1ChCl/2Gly 78 2 o-(MeO)C6H4 Me vinyl 1ChCl/2H2O 2a 57
4 2 1ChCl/2EG 55 3 o-(MeO)C6H4 Me Et 1ChCl/2Gly 2b 64
5 2 1ChCl/2H2O 57 4 o-(MeO)C6H4 Me Et 1ChCl/2H2O 2b 73
6[d] 2 1ChCl/2Urea 67 5 Ph Ph vinyl 1ChCl/2Gly 2c 69
7[d] 2 1ChCl/2LA 30 6 Ph Ph vinyl 1ChCl/2H2O 2c 44
8[e] 2 1ChCl/2Gly 60 7[c] Ph Ph Et 1ChCl/2Gly 2d 24 [46]
[a] Reactions done in air at room temperature using 1 g of DES. Reaction 8[c] Ph Ph Et 1ChCl/2H2O 2d 19 [46]
time 2–3 s. 1 mmol of the ketone used. [b] A commercially available 1.0 m 9 CH3(CH2)2 Me vinyl 1ChCl/2Gly 2e 79
solution of vinylmagnesium bromide in THF was used. [c] Determined by 10 CH3(CH2)2 Me vinyl 1ChCl/2H2O 2e 87
GC and 1H NMR spectroscopy. [d] Addition of the Grignard reagent to 11 o-(MeO)C6H4 Me ethynyl 1ChCl/2Gly 2f 77
urea or LA was also seen. [e] Ethereal solvent removed by exhaustive 12 o-(MeO)C6H4 Me ethynyl 1ChCl/2H2O 2f 72
evacuation. [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 1.0 m solutions of the relevant Grignard reagents in THF
of the relevant tertiary alcohol 2 a was observed in all cases, (2 mmol) were employed. [b] Determined by GC and 1H NMR spec-
finding a significantly improved yield of 78 % when two e- troscopy. [c] Formation of diphenylmethanol (3), resulting from the
reduction reaction was also observed, with yields displayed in brackets.
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 2 a occurs chemoselectively with no compiled in Table 1, the addition reactions in both eutectic
side products observed in the crude reaction mixture (only mixtures were completed in exceptionally short reaction
unreacted starting material 1 a). Remarkably, when the times (2–3 seconds), with in most cases a high degree of
reaction was carried out using water as a solvent, 2 a was selectivity, recovering only unreacted ketone. An exception
obtained in a diminished 21 % yield, indicating that the was the reaction of EtMgCl with benzophenone (1 b)
addition reaction to 2 a must be significantly slower under (entries 7 and 8, Table 2) where the corresponding reduction
these conditions than with the DES, which translates in product (diphenylmethanol, 3) was also formed.[12] Consider-
a greater degree of hydrolysis of the organometallic ing first the two different eutectic mixtures employed,
reagent.[10] Interestingly, using H-donors bearing carbonyl although no direct correlation was found between the H-
functionalities to generate the DES mixtures [urea (entry 6) bond donor component of the DESs (Gly or water) and the
or lactic acid (LA, entry 7)] has a negative effect in the overall outcome of the reaction, in general, better yields for the
chemoselectivity of the addition process, yielding 2 a in 67 and corresponding alcohols 2 were obtained in the Gly-containing
30 % respectively, along with products generated by addition eutectic mixture (odd entries in Table 2). Using vinylmagne-
of Grignard reagent to the C=O bond of these H-donor sium bromide as an alkenylating reagent tertiary alcohols 2 a,
molecules.[11] Crucially the use of Schlenk techniques (N2 or 2 c, and 2 e can be effectively obtained from reactions with 2’-
Ar atmosphere) or low temperatures (0 8C) is not required. In methoxy-acetophenone (1 a) (entries 1 and 2), benzophenone
this sense and since DESs have high heat capacities, low (1 b) (entries 5 and 6), and aliphatic ketone 2-pentanone (1 c)

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(entries 9 and 10), respectively. Similarly ethynylmagnesium

bromide reacts with 1 a, 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 2 b 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 2 d was
obtained in modest yields, similar to those previously
reported for the same reaction using dry THF as solvent at Figure 2. Molecular structure of 4. Displacement ellipsoids are drawn
at the 50 % probability level. Hydrogen atoms have been omitted for
0 8C.[4c]
clarity.
Theoretical and experimental studies monitoring the
addition reactions of carbonyl compounds by Grignard
reagents, using neat water as a solvent, have shown that of highly reactive magnesiate species as chemoselective
while for allyl Grignard reagents additions take place at reagents for additions to ketones has been previously
a comparable rate to those of the competing hydrolysis described, but as far as we are aware, this involves the
processes,[10] alkyl analogs, such as BuMgCl, are much more in situ formation of a bimetallic reagent, by co-complexation
kinetically retarded (addition reaction is up to 105 times of the Grignard reagent with an organolithium.[5] These
slower),[13] and therefore protonation occurs preferentially, lithium magnesiates exhibit greater kinetic reactivities and
yielding only trace amounts of addition products. This unique selectivity profiles, unmatched by conventional mag-
behavior contrasts sharply with the reactions mentioned nesium reagents.[15] Although the formation of a similar
above with EtMgCl and 1 a where in both eutectic mixtures compound to 4 using ammonium salt ChCl present in the
(1ChCl/2Gly and 1ChCl/2H2O), the tertiary alcohol 2 b is the DESs employed in this work could not be demonstrated, the
major product (entries 3 and 4 Table 2), hinting at some type possibility of the participation of more nucleophilic magnesi-
of kinetic activation of the Grignard reagent may be occurring ate species in the addition reactions described in Tables 1 and
using the DESs. Furthermore in this case the conversions 2 cannot be disregarded. This would imply that ChCl may
observed for 2 b are greater than that found when 1 a is have a double role in these processes, as a component of the
reacted at 78 8C in dry THF under strictly inert atmosphere DES mixture employed but also as part of organometallic
techniques (45 %). Germane to this work, Song has recently alkylating reagent, being a halide source.
shown that catalytic amounts of ammonium salt NBu4Cl in To probe the scope of DESs in terms of the nature of the
THF solutions of Grignard reagents can greatly enhance the polar organometallic reagent employed we then studied the
chemoselectivity of addition reactions, minimizing formation reactivity of ketones 1 a–c with a series of organolithium
of enolization and reduction products.[14] The authors pro- reagents (Table 3). The large increase in the polarity of the
posed that substoichiometric amounts of the salt can shift the metal carbon bonds in these commodity reagents when
position of the Schlenk equilibrium of Grignard reagents to compared with organomagnesium compounds, generally
form dinuclear R2Mg·MgX2 species which would favor imposes the use of much lower temperatures in order to
addition. Since a main component in the eutectic mixtures control their selectivity.[1] Thus, for example the addition of
employed in this work is an ammonium salt, a related BuLi to acetophenone should be performed at 78 8C in THF,
activation effect can be operative. To explore this possibility and even so the tertiary alcohol is obtained in a 62 % yield
more, we reacted choline chloride (ChCl) with various along with 7 % yield of the unwanted aldol condensation
amounts of the Grignard reagent Me3SiCH2MgCl in THF product.[5] Contrastingly, under the previously optimized
solvent. However, because of the poor solubility of this reaction conditions used for Grignard reagents (ChCl-based
ammonium salt in this organic solvent, no reaction was eutectic mixtures as solvent, at room temperature in air;
observed. In contrast, the addition of one equivalent of Table 3), BuLi can be added instantaneously to 2-methoxy-
Grignard to the slightly more soluble NBu4Cl afforded acetophenone (1 a) to give tertiary alcohol 2 g in impressive
a solution that deposited crystals of magnesiate [{NBu4}+- yields (60–82 %, entries 1, 2, and 3) without forming any other
{(THF)MgCl2(CH2SiMe3)} ] (4) in a 87 % yield. by-products. We believe this makes our study unique in that it
X-ray crystallographic studies established that the molec- is the first to report the successful coexistence of organo-
ular structure of 4 (Figure 2) is surprisingly a monomer, lithium reagents and green solvents within the same solution.
comprising a well-defined magnesiate anion, made up of a Mg Again and as previously demonstrated for Grignard reagents,
atom which binds terminally to an alkyl group, two chlorines, the addition reaction of BuLi is orders of magnitude faster
and a THF molecule, and a tetrabutylamonium counterion. than its protonation by water, ethylene glycol or glycerol
1
H DOSY NMR studies on solutions of 4 in [D8]THF present in the DES. Showing the general applicability of this
confirmed that this structure is retained. These results suggest approach, chemoselective butylation was also observed for
that these activating effects of the ammonium salts in THF the exclusively aliphatic ketone 1 c (entries 6 and 7 in Table 3)
solutions may be best rationalized in terms of the formation of in either Gly- or water-containing eutectic mixtures. Diverg-
an anionic species which should have an enhanced nucleo- ing from the low conversions observed in the reactions of
philic power over that of a neutral Grignard reagent. The use EtMgCl with benzophenone (1 b) (entries 7 and 8 in Table 2),

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Table 3: Addition of organolithium (RLi) reagents to ketones 1 a–1 c in Information). Although the chemical shifts observed for the
ChCl-based eutectic mixtures.[a] 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
entry R1 R2 R3 DES Yield [%] of 2[b] product, which is consistent with a marked change in the
1 o-(MeO)C6H4 Me Bu 1ChCl/2Gly 2g 71[e] metal coordination sphere. Interestingly, the integration of
2 o-(MeO)C6H4 Me Bu 1ChCl/2H2O 2g 82 the ammonium butyl groups against the monosilyl group
3 o-(MeO)C6H4 Me Bu 1ChCl/2EG 2g 60 revealed a 2:1 NBu4/CH2SiMe2 ratio which would be con-
4[c] Ph Ph Bu 1ChCl/2Gly 2h 75 (12)
sistent with forming a dianionic halolithiate [{NBu4}2+{LiCl2-
5[c] Ph Ph Bu 1ChCl/2H2O 2h 68 (9)
6 CH3(CH2)2 Me Bu 1ChCl/2Gly 2i 73 (CH2SiMe3)}2 ], where two Cl anions have been transferred
7 CH3(CH2)2 Me Bu 1ChCl/2H2O 2i 85 to lithium. The addition of LiCl to lithium amides or
8 o-(MeO)C6H4 Me Ph 1ChCl/2Gly 2j 80 organolithium reagents has a profound effect on their
9 o-(MeO)C6H4 Me Ph 1ChCl/2H2O 2j 82 reactivity. Thus kinetic studies have shown that by adding
10 Ph Ph Ph 1ChCl/2Gly 2k 81 less than 1 mol % of LiCl to lithium diisopropylamide, its 1,4-
11 Ph Ph Ph 1ChCl/2H2O 2k 85 addition reaction to unsaturated ethers occurs 70 times
12 CH3(CH2)2 Me Ph 1ChCl/2Gly 2l 72
faster.[16] A similar halide-mediated accelerating effect could
13 CH3(CH2)2 Me Ph 1ChCl/2H2O 2l 90
14d CH3(CH2)2 Me ethynyl 1ChCl/2H2O 2m 84 also favor the addition reaction in DES over the competing
protonation process.
[a] Reactions performed under air, at room temperature using 1 g of the
In summary, this work introduces deep eutectic solvents as
DES. Reaction time 2–3 s. 1 mmol of ketone used. Commercially
available 1.6 m solution in hexane of BuLi and 1.8 m solution in superior green and biorenewable reaction media for highly
dibutylether of PhLi (2 mmol in all cases) were employed. [b] Determined polar organometallic compounds. As illustrated with both
by GC and 1H NMR spectroscopy. [c] Formation of the reduction Grignard and organolithium reagents, these eutectic mixtures
product 3 was also observed. [d] Lithium acetylide ethylenediamine are the solvents of choice to cross the frontiers between
complex in the absence of organic solvents was employed. [e] Removing synthetically useful main group chemistry and green solvents.
most of the hexane under vacuum from the commercial BuLi solution A comparison of the reactivity profiles of these reagents in
did not affect the selectivity of the addition reaction although 2 g was
DES mixtures with those in pure water, suggest that a kinetic
obtained in a slightly lower yield (66 %).
activation of the alkylating reagents occurs in the former,
favoring nucleophilic addition over the competing hydrolysis
the addition of BuLi to this sensitive ketone formed the process. Building on recent work on the enhanced reactivity
relevant tertiary alcohol 2 h in much greater yields, although of Grignard reagents on the addition of ammonium salts,
small amounts of reduction product 3 could also be detected a plausible rationale may be the in situ formation of anionic
in reaction mixtures (entries 4 and 5 in Table 3). Besides halide-rich magnesiate or lithiate species. Clearly, this first
aliphatic ones, aromatic organolithium reagents (PhLi) can crossing opens up a new, much sought after frontier of
also be successfully added to both aromatic (entries 8–11 in organolithium chemistry in their practical application under
Table 3) and aliphatic (entries 12 and 13 in Table 3) sub- environmentally friendly conditions (green solvents, room
strates.[12] Trying to push our system to its limits, the temperature, and in the presence of air).
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
2H2O and 2-pentanone (entry 14 in Table 3). Astonishingly, Full experimental details are included in Supporting Information.
almost quantitative (84 %) formation of the desired prop- CCDC 978224 (4) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
argylic alcohol was seen, confirming that addition can be also
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
performed in pure eutectic mixtures. It should be noted that data_request/cif.
the same reaction tested using H2O as a solvent gave ketone
2 m in a modest 7 % yield, which hints at a possible activation Received: January 27, 2014
effect of the organolithium reagent when it is added to the Published online: April 25, 2014
DES mixtures.
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
.
Keywords: addition reactions · deep eutectic solvents ·
green chemistry · Grignard reagents · organolithium compounds

of a complex, the addition of one molar equivalent of

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