Introducing Glycerol as a Sustainable Solvent to Organolithium Chemistry: Ultrafast Chemoselective Addition of Aryllithium Reagents to Nitriles under Air and at Ambient Temperature

Article abstract of DOI:10.1002/chem.201705577

Edging closer towards developing air and moisture compatible polar organometallic chemistry, the chemoselective and ultrafast addition of a range of aryllithium reagents to nitriles has been accomplished by using glycerol as a solvent, at ambient temperature in the presence of air, establishing a novel sustainable access to aromatic ketones. Addition reactions occur heterogeneously (“on glycerol conditions”), where the lack of solubility of the nitriles in glycerol and the ability of the latter to form strong intermolecular hydrogen bonds seem key to favouring nucleophilic addition over competitive hydrolysis. Remarkably, PhLi exhibits a greater resistance to hydrolysis working “on glycerol” conditions than “on water”. Introducing glycerol as a new solvent in organolithium chemistry unlocks a myriad of opportunities for developing more sustainable, air and moisture tolerant main-group-metal-mediated organic synthesis.

Full text of DOI:10.1002/chem.201705577

A Journal of
Accepted Article
Title: Introducing Glycerol as a Sustainable Solvent to Organolithium
Chemistry: Ultrafast Chemoselective Addition of Aryllithium
Reagents to Nitriles Under Air and at Ambient Temperature
Authors: Eva Hevia, Maria J Rodriguez-Alvarez, Joaquin Garcia-
Alvarez, Marina Uzelac, Michael Fairley, and Charles T.
O'Hara
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To be cited as: Chem. Eur. J. 10.1002/chem.201705577
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Introducing Glycerol as a Sustainable Solvent to Organolithium
Chemistry: Ultrafast Chemoselective Addition of Aryllithium
Reagents to Nitriles Under Air and at Ambient Temperature
María J. Rodríguez-Álvarez,[a] Joaquín García-Álvarez,*[a] Marina Uzelac,[b] Michael Fairley,[b] Charles T.
O’Hara[b] and Eva Hevia*[b]
Abstract: Edging closer towards developing air and moisture
compatible polar organometallic chemistry, the chemoselective and
ultrafast addition of a range of aryllithium reagents to nitriles has
Making inroads towards meeting this challenge, our groups
have uncovered the potential of Deep Eutectic Solvents (DESs),
combining the non-toxic and biorenewable ammonium salt
choline chloride (ChCl), [Me3NCH2CH2OH]+Cl- with water or
glycerol (Gly),[4] as alternative green reaction media for highly-
polarized organometallic compounds.[5,6] Thus, we have reported
the chemoselective alkylation of ketones by RMgX and RLi
reagents at ambient temperature, under air and in protic DESs,
been accomplished using glycerol as
a solvent, at ambient
temperature in the presence of air, establishing a novel sustainable
access to aromatic ketones. Addition reactions occur
heterogeneously (“on glycerol conditions”), where the lack of
solubility of the nitriles in glycerol and the ability of the latter to form
strong intermolecular H-bonds seem key to favouring nucleophilic
addition over competitive hydrolysis. Remarkably, PhLi exhibits a
greater resistance to hydrolysis working “on glycerol” conditions than
“on water”. Introducing glycerol as a new solvent in organolithium
chemistry unlocks a myriad of opportunities for developing more
sustainable, air and moisture tolerant main-group-metal-mediated
organic synthesis.
a
trio of conditions seemingly incompatible with polar
organometallics, yet bizarrely these offer improved yields and
better selectivities than under standard inert atmosphere
protocols (Scheme 1).[5a] Interestingly, we have found the same
behaviour
for
the
chemoselective
nucleophilic
arylation/alkylation of non-activated imines.[6] The DESs’
success has been attributed to the possible formation of
kinetically-activated mixed-ammonium ate salts by co-
complexation of the polar reagents (RLi or RMgX) with choline
chloride (ChCl). In parallel with these studies, Capriati and co-
workers[7] have demonstrated that Grignard and organolithium
reagents can smoothly undergo nucleophilic additions to γ-
chloroketones or imines “on water”,[8] competitively with
protonolysis, under batch conditions at ambient temperature and
in the presence of air.
Introduction
Celebrating the 100 year anniversary since Schlenk and Holtz’s
discovery of them in 1917, organolithium compounds have been
and remain pivotal to the development of synthetic chemistry.[1]
Staple reagents in academic laboratories worldwide, these
centurions are in high demand in chemical industries that require
manipulation of aromatic scaffolds (e.g., agrochemicals,
pharmaceuticals).[2] This extensive utilization reflects the high
reactivity (and associated oxophilicity) of their Li-C bonds due
largely to the substantial polarity separation between lithium and
carbon. To control this reactivity therefore necessitates the
imposition of severely restrictive protocols (e.g., moisture- and
oxygen-free organic solvents, inert atmospheres, low
temperatures etc.).[1] Thus, running organolithium chemistry
under aerobic and/or hydrous conditions, without the need of
scrupulously dry toxic organic solvents, is one of the ultimate
challenges for synthetic chemists working in this area.[3]
DES
(1ChCl/2H2O)
OH
O
N
Cl
HO
EtMgX
+
Me
Ar
Et
Ar
rt, under air,
choline chloride
Me
3 s
(ChCl)
Scheme 1 Addition of RMgX reagents to ketones under air at ambient
temperature using ChCl-based DESs.[5a]
Biomass-derived solvents [e.g., 2-methyl-THF (Me-THF),
lactic acid, γ-valerolactone or glycerol] are also emerging as
greener alternatives to volatile organic compounds (VOCs) in
organic synthesis.[9] Obtained as a major by-product of the
biodiesel industry,[10] glycerol (Gly) is a particularly appealing
green solvent.[11] Thus along with its exceptional
physicochemical properties (i.e., high boiling point and polarity;
low toxicity and flammability) and its ability to dissolve both
inorganic or organic compounds,[11] recent reports have shown
that using Gly as a solvent can improve the selectivity/efficiency
of organic transformations.[12] Nevertheless, despite these key
advantages, Gly has never been used as a solvent in
organolithium chemistry, probably as a consequence of the
common assumption that these polar reagents will rapidly
decompose in this solvent through reaction with its acidic
alcohol groups.
[a]
M. J. Rodríguez-Álvarez, Dr. J. García-Álvarez
Laboratorio de Compuestos Organometálicos y Catálisis (Unidad
Asociada al CSIC). Centro de Innovación en Química Avanzada
(ORFEO-CINQA)
Departamento de Química Orgánica e Inorgánica (IUQOEM)
Facultad de Química, Universidad de Oviedo,
E-33071, Oviedo, Spain.
E-mail: garciajoaquin@uniovi.es
[b]
Dr. M. Uzelac, M. Fairley, Dr. C. T. O’Hara, Prof. E. Hevia
WestCHEM, Department of Pure and Applied Chemistry
University of Strathclyde, Glasgow, UK, G1 1XL
E-mail: eva.hevia@strath.ac.uk
Supporting information for this article is given via a link at the end of
the document
Taking an important step further on our journey to develop
more sustainable polar organometallic chemistry, here we
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present a breakthrough in the addition of aryllithium reagents to
aromatic nitriles to access a range of bis(aryl) ketones under air,
at ambient temperature by introducing Gly as an environmentally
benign solvent for these reaction classes. For comparison, the
reactions have also been assessed using water as a solvent.
One pot acidic hydrolysis[15] of 2a led to the formation of
benzophenone (3a) in an 83% yield under standard bench
conditions (Table 1, entry 1). Thus, we envisioned that a
modular combination of the PhLi addition to nitriles in Gly with
the in situ hydrolysis of the relevant imine should allow us to
design a straightforward, one-pot method to prepare a library of
structurally diverse ketones under mild, simple and
environmentally friendly reaction conditions (see Tables 1 and 2).
Ketone 3a was obtained in comparable yields using bulk Gly
as a solvent and its chloride-based eutectic mixture 1ChCl/2Gly
(83 and 71% yield respectively, entries 1-2, Table 1). It should
be noted that benzonitrile (1a) is sparingly soluble in both
reaction media, and the reactions take place under
Results and Discussion
To begin, we selected as a model reaction the addition of
phenyllithium (PhLi) to benzonitrile[13] (1a) at ambient
temperature, in air and using different stoichiometries in Gly as
solvent (Scheme 2). Remarkably, the high yield (85%) and
almost instantaneous (3 s) formation of benzophenone imine
(2a) was observed when 2 eq. of PhLi were used. It is important
to note that firstly, using a larger excess of PhLi (2.5-3.0
equivalents) does not improve the yield of benzophenone imine
(2a), but produces small amounts of biphenyl and phenol as by-
products; and secondly, that formation of the tertiary carbamine
(triphenylmethanamine) through double addition of PhLi to
benzonitrile was not observed.[14] However the most remarkable
aspect of this reaction is that the use of inert-atmosphere
Schlenk techniques or low temperatures, i.e., standard reaction
conditions for manipulating organolithium reagents, is not
required.
heterogeneous conditions, when
a completely immiscible
ethereal solution of PhLi is added to a suspension of 1a in Gly. A
similar scenario has been reported by Capriati using
organolithium and Grignard reagents in heterogeneous aqueous
media,[7] with addition reactions taking place “on water”
conditions,[8] rather than in the reaction medium, preferentially
furnishing the relevant addition products instead of the
hydrolysis of the organometallic reagent. “On water” reactions
are thought to occur at the organic/liquid water interface with
water insoluble reactants.[8c] To try to verify this “on glycerol”
assumption we run in parallel three sets of reactions under the
previously optimised reaction conditions (2 eq. of PhLi, ambient
temperature and under air). Thus, firstly we replace glycerol by
the another protic medium (water, entry 3) in which benzonitrile
is insoluble.[7b] Under these “heterogeneous” conditions the
expected ketone 3a could also be produced in good yields (79%,
entry 3), without observing the expected protonation of PhLi as a
competing process. Moreover and in the same line, we observed
experimentally a direct relationship between the solubility of
benzonitrile in other protic and alcoholic reaction media
[ethylene glycol (EG) partially soluble; MeOH totally soluble] and
reaction yield (53 and 8% respectively, entries 4-5), which
suggest a key role for the solubility of the reactant in promoting
these addition reactions. The ability of these alcohols to
engage in H-bonding should also be considered, with that of
MeOH being significantly more limited than those reported for
Gly or water,[16] which can also favour the competing hydrolysis
of PhLi over the addition process. Thus, using Me-THF as a
solvent, in which 1a is completely soluble, under air and at
ambient temperature, afforded 3a in a 47% yield (entry 7).
Further support for “on Gly” reactivity was found when PhLi
addition to 1a was performed in Gly with no stirring. Previous
reports have shown that the yields of “on water” reactions can
be affected by stirring/agitation effects since they can influence
the volume and surface area of the organic droplets.[8c] Under
these conditions, the yield for 3a dropped to 51% (entry 6).
The reactivity of 1a with other polar organometallics (RLi or
RMgX) under the optimized reaction conditions (2 eq., ambient
temperature, under air) was also investigated using glycerol as
solvent. In this sense, aliphatic and more basic organolithium
reagent (nBuLi, entry 8) yielded the expected butylated ketone
3b in a modest 22% yield. Replacing Gly by water afforded 3b
in a slightly improved 37% yield. These findings contrast with
recent work by Capriati for additions of alkyl organolithiums (e.g.
nBuLi) to nitriles under “on water” conditions, which in the
presence of allyl Grignard reagents allows access to tertiary
carbimines.[7b]
NH
N
n
2a (%)
77
80
85
85
C
n eq. PhLi
1.0
1.5
2.0
2.5
3.0
Gly
rt, under air!
1a
2a
OH
85
Gly =
HO
OH
Scheme 2 Study of the addition reaction of PhLi to benzonitrile (1a) employing
different stoichiometries in Gly as solvent (yields determined by GC analysis of
reaction mixtures using a calibration curve).
Table 1. Addition reaction of polar organometallic reagents (RM) to
benzonitrile (1a) in different green solvents.[a]
Entry
RM[b]
Solvent
Ketone
Yield [%]c
1
2
PhLi
PhLi
Gly
1ChCl/2Gly
H2O
3a
3a
3a
3a
3a
3a
3a
3b
3a
3a
83
71
3
PhLi
79
4
PhLi
Ethylene Glycol
MeOH
53
5
PhLi
8
6
PhLi
Gly (without stirring)
Me-THF
51
7
PhLi
47
8
nBuLi
PhMgBr
PhMgBr
Gly
22
9
Gly
traces
3
10
Me-THF
[a]
Reactions were performed under air, at ambient temperature and using 0.5
[b]
g of the solvent. 0.5 mmol of benzonitrile (1a) was utilised throughout.
Commercial solution of PhLi (1.9 M in dibutyl ether), nBuLi (1.6 M in hexanes)
The less reactive Grignard reagent PhMgBr failed to
produce 3a under the optimized reaction conditions (entry 9),
[c]
and PhMgBr (1.0 M in THF) were used.
Yields determined by 1H NMR
spectroscopy using CH2Br2 as an internal standard.
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suggesting that the higher polarity of Li-C bonds in RLi reagents
(versus C-Mg bonds) is crucial for success in the addition
process.[17] This lack of reactivity was also observed when using
Me-THF under air at ambient temperature (entry 10).
Remarkably the reaction of PhLi with PhCN can also be scaled-
up to 5 mmol scale (using 5 g of Gly as a solvent), yielding
ketone 3a in a 78% yield (see Fig S!2 in SI for details).
group tolerance, without observing other competing side
reactions taking place under the conditions investigated. Steric
effects on the substitution of the nitrile do not seem to have a
major role, observing comparable yields in both solvents when
ortho-, meta- and para-tolunitrile were employed (entries 3-6 and
11-12). The addition of PhLi to a purely aliphatic nitrile
(hexanenitrile) furnished the aryl-alkyl-substituted ketone (1-
phenylhexan-1-one, 3j) in either Gly (60%, entry 17) or water
(65%, entry 18) whereas no addition product can be detected
when acetonitrile is employed. This lack of reactivity is
consistent with the high solubility of this nitrile in both solvents,
precluding “on water” or “on Gly” conditions.[18] It should be
noted that contrastingly, hexanenitrile does not dissolve in Gly.
Recent reports have revealed along with increasing yields, a
considerable rate acceleration can be observed in “on water”
reactions when water insoluble reagents are stirred vigorously
for a short period of time in pure water.[7b,8] While this “on water”
catalysis is still to be fully understood, it has been proposed that
trans-phase H-bonding at water-organic interfaces, promoted by
"dangling" OH groups can be responsible.[19] Later studies by
Beattie and McErlean suggest an alternative explanation,
attributing this “on water” effect to a proton transfer across the
organic/water interphase.[20]
Stimulated by these preliminary results, we next assessed
the scope of this methodology extending our studies to a range
of nitriles (1a-i) using Gly or water as solvents. As shown in
Table 2 and regardless of the solvent employed, in most cases,
the nitriles tested led to the efficient and almost instantaneous (3
s) addition reaction with high chemoselectivity, as only
unreacted nitrile and the final ketone (3a-j) were observed in the
reaction crudes. Comparing the yields observed using water and
Gly as a solvent an interesting trend emerges. For liquid
aromatic nitriles (entries 1-8, Table 2) excellent and comparable
yields are observed for both reaction media (76-86%). However
for solid nitriles (entries 9-16), greater ketone conversions are
observed for water than for Gly. Thus for example using (p-
OMe)C6H4CN formed 3f in a modest 32% yield in Gly vs 84% in
water (entries 9-10). This difference could be attributed to the
different solubilities that these solid nitriles may display in the
different solvents employed. Nevertheless, results summarized
in Table 2 indicate an excellent substrate scope and functional
For Gly, studies using broadband vibrational sum frequency
generation (VSFG) spectroscopy have shown that unlike water,
the surface of pure Gly is almost “flat” without the presence of
“dangling” OH groups to protrude out into the vapour phase.[21]
However, analysis on salty NaBr and NaI Gly solutions have
revealed that bromide and iodide anions perturb the interfacial
gly organization in a similar manner to that found in aqueous
halide salt solutions, leading to an increase of the “dangling” OH
groups at the interphase. This made us ponder whether using
salty Gly solutions we could mimic the ketone conversions
observed in water, focusing on particular in the reaction of (p-
OMe)C6H4CN and PhLi, which works well in water but poorly in
neat gly (84% vs 32% yields for ketone 3f, Table 2, entries 9-10;
Scheme 3). Interestingly, using a 1:8 NaCl to Gly molar ratio
]
Table 2. Addition of PhLi to various nitriles (1a-i) on glycerol or water.[a
Entry
R-CN[b]
Product
Solvent
Yield [%]c
1
2
Ph
3a
3a
3c
3c
3d
3d
3e
3e
3f
Gly
H2O
Gly
83
79
81
82
87
80
76
86
32
84
63
90
24
59
43
76
60
65
Ph
3
(m-Me)C6H4
(m-Me)C6H4
(o-Me)C6H4
(o-Me)C6H4
(o-F)C6H4
solution[22] as
a reaction medium lead to slightly lower
4
H2O
Gly
conversions than when using neat Gly, affording 3f in a modest
22% yield (see SI for details), suggesting that perturbing the
interfacial Gly organization does not seem to affect the efficiency
of the addition process (Scheme 3). Further support was found
when performing the addition of PhLi to PhCN in this salty Gly
solution which gave ketone 3a in a 77%, only slightly lower than
using neat Gly (83%, Table 2 entry 1).
For comparison we also assessed this reaction using
H2O/Gly mixtures for the reaction of (p-OMe)C6H4CN and PhLi
to form ketone 3f. As shown in Scheme 3, using a 1:1 mixture
gave 3f in an 58% yield, which is greater than that observed in
neat Gly but lower than in neat water. Contrastingly, using a
10H2O/1Gly mixture led to the formation of 3f in an improved
70% yield (see SI for details). While these differences could be
related to the different dynamics of the complex H-bonding
networks in these mixtures,[23] the different solubilities of the
solid nitrile (p-OMe)C6H4CN in these solvent systems may also
be key.
5
6
H2O
Gly
7
8
(o-F)C6H4
H2O
Gly
9
(p-OMe)C6H4
(p-OMe)C6H4
(p-Me)C6H4
(p-Me)C6H4
(p-Br)C6H4
(p-Br)C6H4
(2-CF3-4-F)C6H3
(2-CF3-4-F)C6H3
n-hexyl
10
11
12
13
14
15
16
17
18
3f
H2O
Gly
3g
3g
3h
3h
3i
H2O
Gly
H2O
Gly
3i
H2O
Gly
3j
n-hexyl
3j
H2O
[ [a] Reactions were performed under air, at ambient temperature and using
0.5 g of the solvent. A commercial solution of PhLi (1.9 M in dibutyl ether)
was added. [b] 0.5 mmol of the desired nitrile (1a-i) was utilised throughout.
[c]
Yields determined by 1H NMR spectroscopy using CH2Br2 as an internal
standard.
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Scheme 4 Assessing the formation of 3a in water and Gly when the order of
addition of reagents is reversed. Yields determined by 1H NMR spectroscopy
using CH2Br2 as an internal standard.
Scheme 3 Assessing the formation of 3f in NaCl/Gly and H2O/Gly mixtures.
Yields determined by 1H NMR spectroscopy using CH2Br2 as an internal
standard.
Intrigued by these findings we pondered whether Gly could
also be used as a solvent for the addition of aryllithiums to
ketones under air, a reactivity that we have previously reported
using water and Gly-based DESs. Pleasingly, tertiary alcohols
4a-c were obtained in good yields (56-80%) as the result of the
chemoselective arylation of benzophenone, acetophenone and
trifluoromethyl acetophenone respectively using PhLi (2 eq) and
bulk Gly as the reaction media (see Scheme 5).
Next, we extended this greener and air-tolerant protocol to
other arylithium reagents, containing both electron-donating [Me
(entries 1-2); MeO (entries 5-6)] or electron-withdrawing [CF3
(entries 7-8)] substituents (see Table 3). Thus, benzonitrile (1a)
was chosen as the benchmark reagent for this study working
under the previously optimised reaction conditions (2 eq. of RLi,
ambient temperature, under air) with Gly or water as reaction
media. As previously observed in Table 2, addition reactions
took place instantaneously (3 s) to benzonitrile furnishing the
non-symmetric diarylketones 3c,k-m in good yields (43-95%)
and remarkable chemoselectivites, as no by-products were seen
in the reaction crudes. In general, for these reactions Gly
appeared to be a superior solvent, with the most noticeable
effect on the yield of 3l, which decreases drastically from 93%
using Gly to 45% in water (entries 5-6, Table 3).
Scheme 5 Addition of PhLi to different ketones in Gly, at ambient temperature
and in the presence of air. Yields determined by 1H NMR spectroscopy using
CH2Br2 as an internal standard.
Table 3. Addition of different aryllithium (ArLi) reagents to benzonitrile (1a)
“on” glycerol or water.[a]
Conclusions
In summary, we have demonstrated that, like water, Gly can
function as an environmentally-friendly reaction medium for the
ultrafast and chemoselective addition of arylithium reagents to
nitriles under standard bench reaction conditions (ambient
temperature and under air), that for almost a century have been
out of bounds in polar organometallic chemistry. Notably working
under heterogeneous conditions (since the starting nitriles are
insoluble in Gly or water) allowed the smooth nucleophilic
addition of organolithium reagents to nitriles either “on glycerol”
or “on water”, respectively. Moreover, the unprecedented use of
Gly (low-cost and renewable feedstock) in polar organometallic
chemistry unlocks countless scenarios for developing more
sustainable main-group-mediated organic syntheses.
Entry
ArLi[b]
Product
Solvent
Yield [%][c]
1
2
3
4
5
6
7
8
(m-Me)C6H4
(m-Me)C6H4
(m-F)C6H4
3c
3c
3k
3k
3l
Gly
H2O
Gly
86
79
59
69
93
43
79
77
(m-F)C6H4
H2O
Gly
(o-OMe)C6H4
(o-OMe)C6H4
[3,5-(CF3)2]C6H3
[3,5-(CF3)2]C6H3
3l
H2O
Gly
3m
3m
Experimental Section
H2O
General procedure for the addition reactions of PhLi with nitriles in
alternative solvent: Syntheses were performed under air and at room
temperature. In a glass tube, the appropriate nitrile (0.5 mmol) was
added to the corresponding alternative solvent (0.5 g) under air, followed
by the addition of PhLi (1 mmol) at room temperature, and the reaction
mixture was stirred for 2-3 seconds. The reaction was then stopped by
addition of a saturated solution of the Rochelle salt (sodium potassium
tartrate tetrahydrate). The reaction mixture was transferred to a round
bottom flask, 5 mL of 2M HCl was added and heated at 100 °C for 30 min.
After cooling down to room temperature, the reaction mixture was
neutralised by addition of NaHCO3 and the organic products were
extracted with dichloromethane (3 x 5 mL). The combined organic
extracts were dried over MgSO4 and the solvent removed under reduced
pressure. Yields of the reaction crudes were determined by 1H NMR
methodology using dibromomethane as an internal standard. The identity
of obtained ketones 3a,[24] 3b,[25] 3c,[24] 3d,[24] 3e,[24] 3f,[24] 3g,[24] 3h,[24]
[a] Reactions were performed under air, at ambient temperature and using 0.5
[b]
g of the solvent. 0.5 mmol of benzonitrile (1a) was utilised throughout. See
[c]
Experimental Section for synthesis of ArLi.
Yields determined by 1H NMR
spectroscopy using CH2Br2 as an internal standard.
Despite these similar performances in water and Gly, a key
difference between these solvents is the greater resistance
towards hydrolysis of ArLi in the latter. This was evidenced when
PhLi was added to the solvent and allowed to stir for 15 seconds
before introducing nitrile 1a. Astonishingly, while only traces of
3a were detected when water was employed, in Gly 3a is formed
in a 74% yield (Scheme 4), which is comparable to that
observed when the order of addition is reversed (83%, Table 2,
entry 1).
3j,[26] 3k,[27] 3l,[24] 3m[28] was assessed by comparison of their 1H and 13
spectroscopic data with those reported in the literature. 3i was isolated
C
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10.1002/chem.201705577
Chemistry - A European Journal
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and fully characterized, see SI for details. All reactions were done in
triplicate to ensure good reproducibility of obtained yields.
[4]
[5]
For recent reviews in DESs see: (a) M. Francisco, A. van den
Bruinhorst, M. C. Kroon, Angew. Chem. Int. Ed. 2013, 52, 3074; (b) E.
L. Smith, A. P. Abbott, K. S. Ryder, Chem. Rev. 2014, 114, 11060; (c) J.
García-Álvarez, Eur. J. Inorg. Chem. 2015, 5147; (d) D. A. Alonso, A.
Baeza, C. Chinchilla, R. G. Guillena, I. M. Pastor, D. J. Ramón, Eur. J.
Org. Chem. 2016, 612.
General procedure for synthesis of aryllithium reagents: In addition
to commercially available PhLi, other aryllithium reagents were tested as
reagents that can undergo addition to benzonitrile. These were prepared
under protective argon atmosphere using standard Schleck techniques
and solvent dried by heating to reflux over sodium benzophenone ketyl
and then distilled under nitrogen prior to use. To a diethyl ether solution
of the chosen aryl iodide (6 mmol in 2.2 mL of Et2O) at -78°C n-
butyllithium (6 mmol, 1.6 M in hexanes) was added drop-wise. The
reaction mixture was warmed up and stirred at room temperature for 2 h
before it was used as a 1M solution of aryllithium reagent for the addition
reactions. Following additions were, as described above, performed
under air in triplicate.
(a) C. Vidal, J. García-Álvarez, A. Hernán-Gómez, A. R. Kennedy, E.
Hevia, Angew. Chem. Int. Ed. 2014, 53, 5969; (b) L. Cicco, M. J.
Rodríguez-Álvarez, F. M. Perna, J. García-Álvarez, V. Capriati, Green
Chem. 2017, 19, 3069.
[6]
[7]
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Acknowledgements
We are indebted to the MINECO of Spain (Projects CTQ2014-
51912-REDC and CTQ2016-75986-P), the Gobierno del
Principado de Asturias (Project GRUPIN14-006) and the
Fundación BBVA for the award of a “Beca Leonardo a
Investigadores y Creadores Culturales 2017” to JGA. We also
thank the EPSRC (EP/N011384/1) and the Society of Spanish
Researchers in the UK (SRUK) and the Fundación Santander
(Emerging Talent Award to EH). The Scottish Funding Council
are thanked for a PECRE award to MF to enable an exchange
visit to Oviedo University.
[14] In contrast, the double addition of RLi/RMgX reagents to nitriles has
been recently reported “in water” and “on water” conditions (see ref. 7b).
[15] See SI for experimental and spectroscopic details.
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[17] Similar trend has been previously reported by us in the addition of
RMgX to imines in different eutectic mixtures, ref. 6.
[18] While in our hands formation of acetophenone, as the result of addition
PhLi to MeCN under the conditions of our study (H2O or Gly as solvent,
rt, under air), could not be detected, it should be noted that Capriati has
reported the sequential addition of PhLi and allylMgCl in water to
acetonitrile furnishing the relevant tertiary allyl amine in a remarkable
70% yield, see reference 7b.
Keywords: Organolithium Reagents • Glycerol • Water • Green
Chemistry • Nitriles •
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Hooked on Glycerol!
M. J. Rodríguez-Álvarez, J. García-
Álvarez,* M. Uzelac, M. Fairley, C. T.
O´Hara and E. Hevia*
Using glycerol as a sustainable and
green reaction medium enables the
efficient chemoselective addition of
aryllithium reagents to nitriles at room
temperature in air, edging closer
towards reaching air- and moisture-
compatible polar organometallic
chemistry
Page No. – Page No.
Introducing Glycerol as a Sustainable
Solvent to Organolithium Chemistry:
Ultrafast Chemoselective Addition of
Aryllithium Reagents to Nitriles Under
Air and at Ambient Temperature
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