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Angew. Chem. Int. Ed. 2023, e202313556
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New Frontiers in Organosodium Chemistry as Sustainable
Alternatives to Organolithium Reagents
David E. Anderson, Andreu Tortajada,* and Eva Hevia*
Dedicated to Professor Dieter Seebach on the occasion of his 86th birthday
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Abstract: With their highly reactive respective C Na and N Na bonds, organosodium and sodium amide reagents could
be viewed as obvious replacements or even superior reagents to the popular, widely utilised organolithiums. However,
they have seen very limited applications in synthesis due mainly to poor solubility in common solvents and their limited
stability. That notwithstanding in recent years there has been a surge of interest in bringing these sustainable metal
reagents into the forefront of organometallics in synthesis. Showcasing the growth in utilisation of organosodium
complexes within several areas of synthetic chemistry, this Minireview discusses promising new methods that have been
recently reported with the goal of taming these powerful reagents. Special emphasis is placed on coordination and
aggregation effects in these reagents which can impart profound changes in their solubility and reactivity. Differences in
observed reactivity between more nucleophilic aryl and alkyl sodium reagents and the less nucleophilic but highly basic
sodium amides are discussed along with current mechanistic understanding of their reactivities. Overall, this review aims
to inspire growth in this exciting field of research to allow for the integration of organosodium complexes within
common important synthetic transformations.
1. Introduction
Ease of synthesis combined with high Brønsted basicity and
solubility in organic solvents has held organolithiums above
other organometallic reagents in synthesis for over
100 years.[1] Their versatile reactivity and widespread applications (as bases, nucleophiles, ligand transfer agents and
more) has inevitably led to the commercialisation of both
organolithium compounds (nBuLi, MeLi, PhLi etc.) as well
as related commodity lithium amides (such as LiDA,
LiHMDS, LiTMP; DA = diisopropylamide; HMDS =
hexamethyldisilazide, TMP = 2,2,6,6-tetramethylpireridide)
derived from bulky secondary amines.[2] In recent years
however, whilst addressing the need to promote sustainability issues in chemistry, research into the more richly
abundant sodium (crustal abundance 22700 ppm vs Li
abundance 18 ppm) has been reinvigorated.[3] The more
ionic highly reactive Na C or Na N bonds in these sodium
compounds gives them the opportunity to be comparable to
or to even surpass their corresponding organolithiums in
terms of reactivity.[4] The challenge is to overcome several
hurdles if organosodium chemistry is to reach the same
levels of applicability as organolithiums, namely the poor
solubility of these reagents in hydrocarbon solvents, and
their poor functional group tolerance and general incompatibility with ethereal solvents when used above cryogenic
temperatures. The cutting edge of polar organometallic
chemistry has recently focused on moving these powerful
Brønsted basic reagents into the limelight, with several
groups currently developing elegant solutions to these
combinations of drawbacks.
[*] D. E. Anderson, Dr. A. Tortajada, Prof. Dr. E. Hevia
Department für Chemie und Biochemie,
Universität Bern
Freiestrasse 3, 3012 Bern (Switzerland)
E-mail: andreu.tortajadanavarro@unibe.ch
eva.hevia@unibe.ch
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It is well established in organolithium chemistry that
addition of Lewis donors to reduce the aggregation of these
polar complexes can have a positive impact on their
solubility and reactivity.[5] Forming smaller aggregates can
enhance kinetic reactivities. In addition, decades of fundamental research on the trapping and characterisation of key
reaction intermediates have led to greater mechanistic
understanding on how organolithium reagents operate, helping the tailoring of synthetic applications. While the
identities of many organosodium intermediates have remained blurred, recent but limited work in the field has
shown the pivotal role of coordination effects in order to
tame the reactivity of these heavier polar organometallic
reagents. Some of this work regarding the use of sodium
dispersions[6] or sodium diisopropylamide[7] in organic synthesis has been recently reviewed. With a wider scope and
showcasing recent examples from the literature, this Minireview focusses on the preparation and uses of organosodium
compounds in synthetic chemistry which have demonstrated
their untapped potential as more sustainable, and in some
cases superior, alternatives to classical organolithium reagents. Special emphasis has been placed on the discussion
of the current mechanistic understanding involved in these
transformations which has helped to rationalise their
observed special reactivities and expand the scope of their
applications. Note that sodium bimetallic compounds have
been well studied over the past twenty years, but this related
work is outside the scope of the present article.[8]
2. Alkyl and Aryl Sodium
Both alkyl and aryl sodium reagents take advantage of their
highly reactive sodium-carbon bonds, forming powerful
Brønsted bases capable of higher reactivity than that of their
related organolithium congeners. Alkylsodium complexes
came into existence 150 years ago and after initial protocols
for their synthesis were reported there was little interest
shown in developing them as useful synthetic reagents in the
decades following.[9a] Early reports for their synthesis called
for the reaction of sodium metal with a haloalkyl or through
the reaction of corresponding diorganomercury complexes
with sodium metal, although, as early as the 1950s the
undesirable use of toxic reagents such as organomercury
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complexes for the synthesis of alkyl- and aryl- sodiums have
been avoided.[9b] The need for specialised reaction conditions to handle these reactive reagents was found with
Morton describing in 1942 an experimental setup for the use
of organosodiums. The flask and rapid stirring was reported
to be key to forming the finely dispersed sodium in Morton’s
protocol.[9c] In more recent years Wagner and Mioskowski
showed that combining a finely divided sodium sand with
aryl chlorides could form powerful alkylsodiums which could
subsequently be useful in directed ortho-metalations, however the resulting alkylsodium complexes were unable to be
isolated and were reacted in situ.[10] In order to form isolable
alkylsodium complexes, these reagents are most commonly
synthesised through alkali metal metathetical exchange of
the congeneric alkyl lithium complex with a sodium alkoxide. This reaction which is driven by the more oxophilic
character of Li vs Na and the lack of solubility of the newly
generated alkylsodium in hydrocarbon solvents, has been
known and widely utilised for decades. Figure 1 depicts the
synthesis of [NaCH2SiMe3]∞,[11] which has been subsequently
isolated as a crystalline solid, exhibiting a polymeric chain
arrangement in the crystal composed of tetrameric
{NaCH2SiMe3}4 units.[12]
In 1985 Schleyer reported the synthesis of nBuNa via
nBuLi/NaOtBu metathesis and its NMR characterisation on
addition of Lewis donors TMEDA (N,N,N’,N’-tetramethylethylenediamine) and THF.[13] Building on these pioneering studies, in 2022 Hevia and co-workers reported a
standard synthetic procedure to access alkyl sodium reagents
which contained a detailed experimental set-up on the safe
formation and isolation of gram-scale quantities of the
sodium alkyl nBuNa and bulky amide NaTMP.[14]
Andreu Tortajada was born in Benaguasil (Valencia, Spain) and moved to
Tarragona, where he obtained his master’s degree and PhD at ICIQ in 2020,
under the supervision of Prof. Ruben
Martin. His doctoral studies focused on
the use of nickel catalysis for the
incorporation of CO2 and isocyanates
into organic substrates. Currently he is a
postdoctoral researcher at the University
of Bern with Prof. Eva Hevia, probing sblock organometallic compounds for
metalation and functionalisation of arenes.
David Anderson was born in Perth, Scotland and completed his master’s degree
at the University of Strathclyde (UK),
Glasgow under the supervision of Prof.
William Kerr. David is currently working
towards his PhD at the University of
Bern under the supervision of Prof. Eva
Hevia where he is researching synthesis
and structure of polar organometallic
reagents with a focus on organosodium
complexes.
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Figure 1. Synthesis and solid-state polymeric structure of NaCH2SiMe3.
RT = Room temperature.
While this RLi/NaOtBu exchange method allows for the
preparation of pure alkylsodium reagents in high yields, it
also comes with the drawback of needing alkyllithium
reagents as precursors. With an emphasis on greener and
more sustainable chemistry, the ability to form and isolate
an organosodium reagent starting from sodium metal and
thus bypassing the need for organolithiums would be a more
atom economical route towards organosodium chemistry.
In 2019 Takai and Asako reported the in situ synthesis of
aryl sodium reagents from reacting aryl chlorides with a fine
sodium dispersion (particle size < 10 μm) under mild reaction conditions (hexane, 0 °C) (Figure 2).[15] Initially they
Eva Hevia completed her Ph.D. degree,
from the Universidad de Oviedo (Spain)
in 2003, under the supervision of the late
Victor Riera. In 2006, after a three-year
appointment at the University of Strathclyde (UK) as a Marie Curie postdoctoral
fellow working with Robert Mulvey, she
gained a Lectureship at the same institution. She then was promoted to full
Professor in 2013. In 2019, Eva moved to
the University of Bern to a Professorship
in Inorganic Chemistry. Research in her
group focuses on polar organometallic
chemistry at the crossroads of inorganic,
organic, and green chemistry.
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Figure 2. Sodium dispersion (SD) mediated transformations to access
in situ alkyl and aryl sodium complexes.
proved the efficiency of the formation of the aryl sodiums
by quenching the formed species in situ with either D2O or
PhMe2SiCl whilst reporting excellent yields after starting
from simple alkyl or aryl substituted aryl chlorides. Substitutions beyond simple alkyls were briefly probed, with the
functional groups methoxy and dimethylamino being tolerated on the aryl chlorides in these initial studies. Looking to
expand this reaction to more decorated molecules, they next
combined this metalation approach with some standard
cross coupling reactions. The sodium reagents could be
transmetalated with less electropositive boron or zinc to be
used in either Suzuki–Miyaura or Negishi coupling reactions. Additionally, aryl sodiums could also be used for the
direct cross-coupling reaction with a palladium catalyst and
aryl bromides albeit with a limited substrate scope.
Building upon their initial study, they next formed an
alkyl sodium in situ and used this in generating the desired
aryl sodium intermediates via a sodium halogen exchange
reaction starting from aryl bromides and iodides (Figure 2).[16] After screening of several alkyl chlorides, it was
found that neopentyl chloride afforded the corresponding
neopentyl sodium with the highest efficiency. The sodium
halogen exchange performed by neopentyl sodium was
reported to work under unusually mild conditions, high
yields were seen using 2 equivalents of the alkyl sodium
reagent at 0 °C for 30 minutes. The scope of aryl sodiums
accessed through this method was much wider than the
scope reported in their previous report, with compounds
containing the more easily reduced polyaromatic and
stilbene groups also being tolerated under these conditions.
Their optimised reaction conditions allowed for multiple
sodiations in single substrates containing more than one
bromide position. As with their previous study, the formed
aryl sodiums could be further transformed to more stable
boronic esters or aryl zincs to be used in cross-coupling
reactions, thus greatly expanding the synthetic potential and
scope of products that could be accessed from these organosodium reactions.
Other groups have also used metallic sodium to mediate
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mation, as well as N Na (see below) and P Na bond
formation as reported by Han and co-workers in 2020.[17]
The Yorimitsu group has exploited related sodium dispersions (particle size < 10 μm) for reductive 1,2-syn diborylation of alkynes using B(OMe)3 (Figure 3a).[18] This sodiummediated reductive functionalisation relies on the lack of
reactivity of the borane electrophile with the Na dispersion.
The authors proposed the initial reduction of the triple bond
by the sodium dispersion to form a radical anion intermediate, generated by single electron transfer (SET) that in turn
can be trapped under mild conditions with borane addition.
A further SET leads to a borylated carbanion, with the
isomer shown in Figure 3a favoured due to the intramolecular coordination of the methoxy oxygen to sodium. A
final reaction with an additional equivalent of B(OMe)3
affords the (Z)-bis(borate) shown in Figure 3, which is
protected from overreduction by the negatively charged
nature of the intermediate. Interestingly it was found that
reduction of diphenylacetylene with sodium dispersion
proceeded much faster that when using lithium sand. This
was partly attributed to the far higher surface area of their
sodium dispersion than that able to be achieved with lithium
sand (120–150 μm diameter). A modified version of this
technique has been used by the Yorimitsu group in the
regioselective preparation of trans-1,2 dimetallo-alkenes in
which they combine sodium dispersion with Mg or Al
reagents to access these highly unstable and reactive
metalated intermediates.[19]
The same group has also extended this procedure in the
difunctionalisation of alkenes similarly noting the superior
power of sodium dispersion over lithium sand for these
reactions (Figure 3b). They propose a radical anion similar
to the one proposed in the reductive diborylation of alkynes
as a possible reaction intermediate in the functionalisation
Figure 3. a) Proposed mechanism for reductive 1,2-syn diborylation of
alkynes. b) Alkali-metal-mediated reductive diborylation of alkenes.
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of aryl alkenes with sodium metal and reduction-resistant
alkoxy substituted electrophiles.[20]
An alternative method of synthesising a powerful alkyl
sodium reagent “on demand” in situ has been described by
Knochel.[21] In this study it is reported that the hydrocarbon
soluble alkyl sodium reagent (2-ethylhexyl)sodium can be
prepared in flow from the passing of a solution of the
corresponding alkyl chloride in hexane through a metallic
sodium packed reactor column under mild conditions (225 s,
25 °C) (Figure 4a). Using an alkyl sodium prepared in these
conditions eliminates the possibility of excess sodium metal
being present in the reaction mixture, which can interfere
with more exotic and easily reduced electrophiles; thus, the
cleanly formed alkyl sodium can be used for more
applications than those formed in batch from an excess of
sodium dispersion. The chosen alkyl sodium was found to be
highly soluble in hexane without the need for Lewis donor
additives for solubilisation, but the alkyl sodium is unstable
in solution after 18 hours due to a suspected β-hydride
elimination pathway.
Utilising this hydrocarbon soluble alkyl sodium under
flow conditions allows for the efficient functionalisation of a
wide range of aryl bromides via direct sodium halogen
exchange which can be performed rapidly at
40 °C
generating in situ a wide range of aryl sodium species. The
functional group tolerance was extended to chloro-, meth-
Figure 4. Synthesis of sodium alkyl NaCH2CH(Et)Bu in flow and its
applications in: a) sodium halogen exchange reaction; and b) benzylic
sodiations.
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oxy- and dimethylamino- substituted aryl bromides. After
an electrophilic quench in batch conditions with a diverse
range of electrophiles, such as ketones, epoxides and alkyl
chlorides, highly functionalised products could be accessed
in excellent yields. It was also reported that sensitive but
synthetically useful bromo-substituted N-containing heterocycles could also undergo sodium halogen exchange under
optimised conditions to afford alcohol and ketone products
after electrophilic quenching.
Moving beyond the sodium halogen exchange, the
Knochel group also reported that their soluble alkyl sodium
reagent was capable of performing sodiations via a sodiummediated direct deprotonative metalation (Figure 4b).[22]
Expanding on their previous work on alkyl sodium reagents
used in flow, they went on to study the metalation of poorly
acidic toluene and xylene derivatives with their hydrocarbon
soluble alkyl sodium reagent under similar flow conditions.
Toluene derivatives substituted with simple alkyl and aryl
groups were well tolerated in the initial metalation step, and
subsequent electrophilic quenches under batch conditions
were performed with a diverse range of electrophiles
including epoxides, ketones, aldehydes, and alkyl halides.
The addition of the Lewis donor TMEDA proved necessary
for reactions with several of their metalated intermediates
due to the lower solubility of the benzyl sodium species
leading to significantly elongated reaction times. Finally, to
showcase the usefulness of the reported synthetic method,
they demonstrated the synthesis of two common drug
molecules, Fingolimod and Salmeterol. Starting from solvent
quantities of p-xylene and toluene-d8 respectively the
molecules were synthesised in a transition-metal-free synthesis, in high yields and over several synthetic steps.
In recent years, research on classical polar organometallic reagents such as RLi or RMgX have noted
compatibility with sustainable deep eutectic solvents (DES)
which contain hydrogen bond donors such as glycerol or
water.[23] Furthermore, sometimes enhanced reactivities and
special regioselectivities have been realised when working in
DES in the presence of air, under experimental conditions
that seemingly go against over 100 years of experience on
the use of these highly reactive reagents. Breaking new
ground in this area, seminal studies by Capriati have
revealed that organosodium reagents can also be used in
DES. Thus, using hexane as a solvent, a range of highly
reactive C(sp3), C(sp2) and C(sp) bonded organosodiums
have been prepared in situ which subsequently undergo
electrophilic interception in DES or even in water as the
reaction medium (Figure 5).[24]
It was initially demonstrated that sodiated anisole could
be formed in hexane from the reaction of elemental sodium
and 2-chloroanisole. Under their optimal conditions of using
4 equivalents of metallic sodium to form 1.8 equivalents of
the sodiated anisole, the formed aryl sodium complex could
be quenched with benzaldehyde under vigorous stirring in a
DES mixture of 1 : 3 L-proline/glycerol (Pro/Gly) in a 94 %
yield. It was noted that the form of sodium was important to
the success of the reaction. Sodium bricks were seen to
outperform sodium dispersion with regards to overall yield
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Figure 5. Reactions of alkyl, aryl and alkynyl sodiums in DES or water
under an aerobic atmosphere.
of the quenched product, with the bricks described as small
pieces of clean sodium cut off from a larger sodium lump.
Chloro- arenes containing methoxy, dimethylamino and
methyl groups could be transformed to the corresponding
aryl sodiums which could then be further functionalised with
simple electrophilic quenches in either DES or water. These
reactions were found to be completed in short times of only
20 s, minimising the opportunities for the competing hydrolysis of these highly reactive organosodium intermediates.
Taking inspiration from Takai and Asako’s initial report,[16]
neopentyl chloride was found to cleanly produce the
corresponding alkyl sodium from the reaction of sodium
metal with the alkyl chloride in hexane. This in situ formed
alkyl sodium actioned either sodium halogen exchange or
direct deprotonation of a range of aryls and alkynes under
mild conditions (0 °C in hexane), the products of which
could be quenched with various simple electrophiles. The
practicality of this reaction was demonstrated by showing
the multi gram synthesis of the anticholinergic drug
orphenadrine in a high yield and over two synthetic steps
(80 % 2.17 g). The promising results from this report have
opened new avenues of research towards more sustainable
applications of organosodium chemistry starting from sodium metal in non-toxic solvents.
As is well established in organometallic chemistry,
structures and coordination environments of the metalated
intermediates can have a profound effect on tuning the
reactivity of polar organometallic reagents. The poor
stability and solubility of alkyl sodium reagents have
hindered full studies into these reactivities. Lately, however,
several reports have shed light on these poorly understood
reaction mechanisms.
In a comprehensive study on the metalation and further
functionalisation of toluene derivatives via a sodiated benzyl
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intermediate, Hevia reported on the solution and solid-state
structures of alkyl sodium and substituted benzyl sodium
intermediates in the aroylation of toluene with Weinreb
amides.[25] Starting from the polymeric unsolvated alkyl
sodium reagent [NaCH2SiMe3]∞ (see above) it was discovered that by addition of the Lewis donors PMDETA
(N,N,N’,N’’,N’’-pentamethyldiethylenetriamine)
or
Me6TREN [tris(N,N-dimethyl-2-amino-ethyl)amine], the
polymer could be broken down into discrete molecular
motifs (Figure 6). The PMDETA adduct crystallises in a
rare trimolecular arrangement of three molecules of
NaCH2SiMe3 solvated by two molecules of PMDETA,
although 1H DOSY NMR studies in C6D12 suggest that in
solution this compound exists as [{NaCH2SiMe3)(PMDETA}2] dimers. Increasing the denticity of the Ndonor led to the isolation of [NaCH2SiMe3(Me6TREN)],
which is monomeric both in solution and in the solid state.[26]
Soluble in hydrocarbon solvents, these powerful alkyl
sodium reagents can metalate near stoichiometric equivalents of toluene and toluene derivatives in hexane under
mild conditions (room temperature, 1 h). These sodiated
toluene intermediates could subsequently be quenched with
Weinreb amides to form the corresponding 2-arylacetophenones (Figure 7). The study compared the reactivity of the
alkyl sodium with that of similar alkyl lithium reagents, and
it was observed that the power of the alkyl sodium bases
was indeed needed in order to metalate the toluene
derivatives under such mild conditions, with only traces of
yield reported when the sodium reagents were replaced with
their lighter, less reactive lithium congeners. In the optimisation of reaction conditions, it was also observed that the
yield of the model reaction with PMDETA was much higher
than that of the reaction using the bidentate TMEDA
ligand, further highlighting the importance on N-donors in
activation of the alkyl sodium. Furthermore, it was reported
that the Lochmann-Schlosser combination of NaOtBu and
LiCH2SiMe3 was less effective at the metalation step than
that of the pure alkyl sodium.
Figure 6. Molecular structures of the crystalline PMDETA and Me6TREN
complexes of NaCH2SiMe3.
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Several of the PMDETA-solvated benzyl sodium intermediates formed in the study were characterised in the solid
state by X-ray crystallography and in solution by 1H DOSY
NMR spectroscopy to probe the mechanism of these
reactions more deeply. Interestingly, while a variety of
structural motifs with different degrees of aggregation were
found in the solid state, 1H DOSY NMR studies in C6D6
support the formation of monomeric arrangements in
solution where it is likely that, in some cases, Na attains
further stabilisation by engaging with the π-cloud of an
arene solvent molecule. One overarching bonding feature
observed in each benzyl sodium species was Na forming π
interactions with the ipso carbon atoms of the benzyl
fragments. This trend has also been observed by Robertson
and Mulvey when reporting the synthesis and characterisation of a homologous series of lithium, sodium, and
potassium benzyl monomers with the tetradentate Lewis
donor Me6TREN (Figure 8).[27] In their insightful study they
reported that the size of the alkali metal cation has a
significant effect on the coordination within the crystal
structure. The smaller lithium cation shows an almost fully σ
bonding characteristic with a short Li Cbenzylic bond of
2.352(3) Å and a long Li Cipso distance of 3.467(3) Å. For
the potassium containing complex, the potassium cation was
seen to be gaining significant π interactions by sitting over
the phenyl ring, seen by the shorter K Cipso bond of 3.098 Å
and elongated K Cbenzylic distance of 3.893 Å. Contrastingly,
the sodium containing complex was observed to be somewhat between the two extremes, gaining σ interactions from
the benzylic carbon (Na Cbenzylic 2.556(1) Å) as well as π
interactions from the phenyl ring (Na Cipso 3.185(1) Å). In
2022 the same group made an in-depth study into the nature
of the bonding of solvated alkali metal cations to di-topic
arylmethyl anions. The study utilised both crystallographic
data and DFT investigations, linking the coordination modes
of the different alkali metals with the electronic nature of
the cations.[28] A related coordination trend has been
reported by the Lu group for the structures of [(Me6TREN)MCH(Ph)SiMe3] (M = Li or Na) in which the isolated Li
containing complex shows σ bonding to the benzylic position
whereas the structure of the Na containing complex shows
exclusively π interactions with the aryl ring. This extreme
case can be attributed to the steric demands present at the
benzylic position of this particular complex.[29]
Studying the reactivity of [NaCH2SiMe3]∞ from a different perspective, the Lu group have reported the reactivity of
the monomer [NaCH2SiMe3(Me6TREN)] in the Peterson
olefination reaction and disclosed divergent reactivity
between the sodium alkyl and its lithium congener (Figure 9).[30,31]
It was shown that [LiCH2SiMe3(Me6TREN)] promotes
nucleophilic addition whereas [NaCH2SiMe3(Me6TREN)]
allows for a subsequent Peterson elimination for the methylenation pathway to occur. Polydentate Me6TREN was
argued to be crucial for the success of these reactions, where
control reactions with no ligand present showed the
formation of the nucleophilic addition product with both
alkali metal alkyl complexes. This reactivity study was
supported by DFT calculations into the reaction pathways
which corroborate their observed reactivity, showing that
olefination is energetically favourable only with the sodium
containing complex. From these calculations it was observed
Figure 8. Overlay of the molecular structures of crystalline Me6TRENsolvated benzyl-lithium, -sodium and -potassium.
Figure 9. Divergent reactivity pathways with carbonyl compounds of
alkyl sodium vs alkyl lithium compounds.
Figure 7. Aroylation of toluene derivatives via sodiated intermediates.
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that the barrier for β-silyl abstraction was higher in the
lithium containing complex than for the sodium complex,
possibly explaining the divergent reactivity within this
system.
3. Sodium Amides
Sterically demanding lithium amides such LiHMDS, LiDA
or LiTMP, have long been widely utilised reagents in
synthetic chemistry, due to their high Brønsted basicity
combined with their poor nucleophilicity.[2] These features
allow for the abstraction of a proton from a substrate while
disfavouring possible competitive nucleophilic attack of
reactive moieties present in the molecule, making them the
ideal reagents to prepare enolates from the corresponding
carbonyl compounds or metalate functionalised aromatic
systems. However, on moving away from the lithium amides
to their heavier analogues, solubility in organic solvents
dramatically decreases due in part to the increased ionicity
of the heavier AM N bonds. In fact, we find that the only
commercial sodium amide is NaHMDS, in which the
presence of two -SiMe3 groups aids its solubility in hydrocarbon solvents. However, the presence of Lewis base
donors has been shown to influence amide solubility,
solution aggregation, and therefore their reactivity.[5] Collum’s group has studied extensively the behaviour of
NaHMDS in solution[32] and its reactivity to form enolates.[33]
In solution it was observed to form dimeric or monomeric
species depending on the coordination abilities of the
solvent (Figure 10a), which had an impact on the formation
of the E or Z enolate that could be achieved with a
challenging non-symmetrical ketone (Figure 10b).
The obtention of less soluble and less stable sodium
bases is evidenced when moving to the synthesis of sodium
diisopropyl amide (NaDA). This amide can be made by
metalation of the parent amine with an alkyl sodium or by
direct metalation using metallic sodium, which requires in
this case the use of N,N-dimethylethylamine as solvent. The
Figure 10. Enolization of ketones mediated by NaHMDS. a) Solution
structures of NaHMDS, b) Enolate formation selectivity with
NaHMDS.
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use of THF or other ethereal solvents induces rapid
decomposition of NaDA in non-cryogenic conditions, and it
is completely insoluble in more inert hydrocarbon solvents.
Collum has extensively studied its solution behaviour and
reactivity,[7] finding that it can react differently to LiDA.
NaDA favours elimination of alkyl bromides to selectively
form the alkene product in dehydrohalogenation reactions
(Figure 11a).[34] Moreover, it mediates the selective isomerisation of allyl ethers to the Z isomer (Figure 11b) or allows
epoxide eliminations at low temperatures (Figure 11c),
reactions that require much harsher conditions when
performed with LiDA.[35]
Sodium diisopropyl amide also features in directed
ortho-metalation reactions, to abstract a proton located
ortho to a halogen atom or methoxy group to form the
corresponding sodiated intermediates at low temperatures
(Figure 12a).[36]
Metalated intermediates in this type of reaction, especially those obtained from heterocycles and more functionalised molecules are generally less stable and difficult to
access. To address this problem, Knochel has reported the
use of flow conditions to form these unstable intermediates
in a very short period of time, then rapidly quenching them
with electrophiles to generate the final functionalised
products (Figure 12b).[37] Starting with a solution of NaDA
in N,N-dimethylethylamine, they could prove that the use of
flow was key for the success of this transformation, since
performing the same reaction at the same temperature in
batch conditions led to the decomposition of the heterocycle
due to the thermal fragility of the sodiated intermediate.
Moreover, expanding further the synthetic potential of this
approach, the same group has recently shown that the use of
a flow system enables the metalation not only of aromatic
species, but also of other conjugated alkenes, such as α,βunsaturated nitriles or vinyl thioethers (Figure 12c).[38]
As alluded to in many examples discussed so far, the use
of Lewis donor molecules has been essential to solubilise
highly reactive organosodium reagents. Polydentate amines
have excelled in this task, due to their coordination abilities,
easy access and robustness. Collum has found that tridentate
Figure 11. A selection of synthetic transformations carried out by
NaDA: a) Dehydrohalogenation, b) allyl ether isomerisation and c)
epoxide elimination.
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Figure 12. Comparative NaDA metalations in a) Direceted ortho Metalation in batch, b) arene and heteroarene metalation in flow, and
c) alkene metalation in flow.
PMDETA can accelerate reactions mediated by NaDA, due
to its ability to help reversibly form monomeric species in
solution, which results in up to a 30-fold acceleration when
PMDETA was used in catalytic amounts for a range of
reactions, such as alkyl bromide elimination or the opening
of epoxides.[39] Another approach to improve the solubility
of sodium amides without significantly compromising their
reactivity has been reported recently by the same group, in
which -SiMe3 and -iPr groups are combined in the nitrogen
center, giving sodium isopropyl(trimethylsilyl)amide. This
base has similar stability in ethereal solvents to the
commercially available LiDA, but with higher reactivity.[40]
To access metalation and functionalisation of less
reactive aromatic systems (in terms of the C H deprotonation), the use of stronger bases is required. Generally, the
TMP amides (TMP = 2,2,6,6-tetramethylpiperidide) present
a higher basicity, due to the presence of four methyl groups
at the alpha positions coupled with their higher steric
congestion provided by this amide backbone. Despite
NaTMP being first reported by Lappert and Mulvey in 1999,
presenting a trimeric structure in the solid state,[41] its use
has been mainly applied to the preparation of magnesium
and zinc bimetallic bases.[42] Surprisingly, the use of NaTMP
in deprotonative metalations without any divalent metal has
been mostly overlooked and just recently some applications
have been described. In 2019, Takai, Asako and co-workers
reported a convenient in situ synthesis of NaTMP from a
dispersion of sodium metal, which allowed them to study
their use in Wittig olefination or in the metalation of some
activated arenes, such as benzothiophene (Figure 13a).[43] In
a related study, Mori and co-workers have reported the use
of sodiated thiophenes by NaTMP in nickel catalysed crossAngew. Chem. Int. Ed. 2023, e202313556 (9 of 13)
Figure 13. Deprotonative metalation of arenes with a) NaTMP prepared
from sodium dispersion or b) NaTMP/Ga(CH2SiMe3)3 combinations.
couplings for formation of polythiophenes.[44] Hevia, Mulvey
and co-workers also reported in 2019 that the stepwise
addition of Ga(CH2SiMe3)3 and NaTMP to anisole in hexane
allows for the ortho-gallation of this substrate in excellent
yields. Mechanistic investigations revealed that sodiation of
anisole initially takes place followed by fast transmetalation
to Ga to form a more stable metalated product.[45] Addition
of TMEDA allows for isolation of sodium gallate
[(TMEDA)Na(OMe-o-C6H4)Ga(CH2SiMe3)3] which was
structurally defined (Figure 13b). Stepwise addition of the
reagents was key in order to minimise side reactions where
NaTMP and the Ga alkyl could react with each other.
Emphasising the synergistic behaviour of this bimetallic
combination, it should be noted that NaTMP in the absence
of the Ga trap metalates anisole only in modest yields
(below 20 % yield after iodination).
Shedding light on the constitutions of the organometallic
intermediates involved in arene metalation using NaTMP in
combination with Lewis donors, the Hevia group has found,
using anisole as a model substrate, that its sodiation in the
presence of TMEDA (or PMDETA) is incomplete and
stable mixed aggregates of the sodiated arene and the
sodium amide are formed in solution (Figure 14). This
intermediate is formed almost instantaneously in 43 % yield,
is stable and even with the presence of free anisole in
solution, the constitution of this reaction mixture does not
change overtime, suggesting that an equilibrium has been
reached.[46] Interestingly, this equilibrium could be altered
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Figure 15. Deprotonative metalation with NaTMP/PMDETA and B(CH2SiMe3)3. a) Deprotonative borylation, b) borata alkene formation.
Figure 14. Deprotonative borylation with NaTMP and B(OiPr)3.
by the addition of a bulky boron-based Lewis acid, which
allowed the formal borylation of the aromatic compounds,
furnishing sodium boronates which could be further coupled
with a palladium catalysed cross-coupling to form the
corresponding biaryls in excellent yields. The formation of
these boronates permitted this coupling to occur without the
need of any additional base, forming the C C bond in a
straightforward manner. Different arenes, such as benzene,
naphthalene, methoxyarenes or fluoroarenes could be
selectively engaged in the deprotonative metalation/crosscoupling reactions. In this case, the use of NaTMP was
crucial since switching to the LiTMP congener resulted in
poor yields of metalation.
These sodium-mediated borylation studies also revealed
the importance of the choice of boron electrophile used.
Thus, if B(OMe)3 was employed the yield for the borylation
of anisole diminishes to 10 %. This is attributed to its
preferential reactivity with NaTMP which depletes the base
present in solution, whereas the steric incompatibility
between NaTMP and B(OiPr)3 favours the quench of the
Na C(Ar) driving the equilibrium towards the sodium
boronate formation.
Interestingly using the even more sterically crowded
borane B(CH2SiMe3)3 uncovered a new reactivity pattern
for NaTMP, where the relevant sodium boronate formed
can undergo a second arylation in the absence of any added
base when reacted with an excess of the corresponding
arene at 80 °C (Figure 15a).[47] This second metalation can be
explained by the high basicity of one of the alkyl groups on
the boron centre, which can be rationalised by the high
steric demand of the CH2SiMe3 groups that positions one of
Angew. Chem. Int. Ed. 2023, e202313556 (10 of 13)
them in close proximity to the sodium centre, as observed in
its crystal structure. DFT calculations support this mechanistic pathway and propose a reactive borata-alkene intermediate that can deprotonate another arene to give the
doubly arylated sodium boronate. Moreover, the use of
NaTMP enabled the formation of a borata-alkene by the
competing deprotonation of the trialkylborane, which could
be shown experimentally and supported by DFT calculations. These reactions were again not replicated when using
the lithium amide, establishing a clear alkali-metal effect
(Figure 15b). This time, instead of obtaining the borataalkene, the lithium borate resulting from metalation of one
of the methyl groups present on the Lewis donor was
obtained.
The general higher reactivity of sodium amides compared with their lithium analogues has allowed the development of novel catalytic transformations. In 2017 Schneider
reported the allylation of imines catalysed by NaHMDS
(Figure 16a).[48] In this example the base deprotonates the
allyl benzene derivative to form the corresponding allylsodium, which could engage in a nucleophilic addition to an
imine to form a C C bond. The resulting sodium amide was
then sufficiently basic to metalate another molecule of
starting material to regenerate the active catalytic species. A
clear alkali-metal effect was observed, where LiHMDS and
KHMDS gave much lower yields. Stronger amides as
LiTMP and NaTMP did not give satisfactory results,
probably due to their instability in ethereal solvents. In
2022, Yamashita, Kobayashi and co-workers reported the
use of LiTMP/KOtBu or LiTMP/NaOtBu to achieve the
same transformation using non-activated allyl motifs, such
as propene.[49]
Studying the reactivity of less hindered amides, the
Hevia group has shown that NaCH2SiMe3 can be used as an
effective precatalyst to mediate the regioselective hydroamination of styrenes using secondary amines such as
piperidine or morpholine (Figure 16b).[50] This transformation is characterised by excellent yields, low catalyst loadings
and compatibility with THF. With the aim of widening the
use of sodium reagents in synthesis, they demonstrated that
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of the arene substrates and C6D6 in solution, allowing the
hydrogen isotope exchange. Proving the ability of NaTMP
to partially deprotonate benzene, they could isolate and
characterise in the solid state the compound
[(TMEDA)2Na3(TMP)2(Ph)], a formal co-complexation of
NaPh with 2 groups of TMEDA·NaTMP. This deuteration
procedure could be extended to a range of substrates, such
as anisole, trimethyl(phenyl)silane, diphenylacetylene or
naphthalene, incorporating deuterium in almost every position of the molecules. One of the main limitations of this
methodology still remains the tolerance to more reactive
functional groups, such as ketones, esters or nitriles. To
understand better this process, the use of polydentate
amines was studied, and it was observed that Lewis-donors
had a great influence, allowing the formation of more
soluble and reactive aggregates for the metalation of arenes.
A clear alkali-metal effect was also present in this transformation, observing just very low deuterium incorporation
when LiTMP was used instead. Other less basic amides,
such as NaHMDS failed to promote this reaction and the
use of more basic alkyl sodium reagents did not show any
deuterium incorporation, showing the crucial role of the
sodium amide for an efficient deuteration. It was proposed
that a reversible metalation of both the substrate and the
solvent is key for an efficient hydrogen isotope exchange,
where the produced small quantity of TMP(H/D) in solution
is essential.
4. Conclusions and Outlook
Figure 16. Recent catalytic transformations involving sodium amides:
a) NaHMDS catalysed imine allylation, b) sodium amide catalysed
hydroamination of styrenes and c) NaTMP/PMDETA catalytic Hydrogen Isotope Exchange (HIE).
this reaction could also be carried out under ambient
conditions. Using stoichiometric amounts of sodium piperidide in 2-MeTHF under air, they observed faster hydroamination reactions than with the lithium analogue. Remarkably, ambient moisture was essential for the success of
the hydroamination reaction, because running the reaction
under inert conditions instead gave polymerisation of the
styrene substrates. The excellent catalytic potential of
organosodium complexes in hydroelementation reactions
has also been demonstrated by Mulvey and co-workers, who
have recently described the effective use of nBuNa as a
precatalyst to promote the hydrophosphinylation of
alkynes.[51]
Moving to the much bulkier NaTMP, the Hevia group
reported its use for catalytic hydrogen isotope exchange,
achieving the perdeuteration of non-activated arenes using
deuterated benzene as deuterium source (Figure 16c).[52]
The success of this approach relies on the partial metalation
Angew. Chem. Int. Ed. 2023, e202313556 (11 of 13)
Organolithium reagents have long been one of the most
utilised organometallic reagents in synthesis, due to their
relative ease of synthesis, their versatility, high Brønsted
basicity and high nucleophilicity. However, recently the
chemical community has started search for more sustainable
alternatives, due to the spiralling cost and potential
disruptions to lithium supply chains.[53] More earth-abundant
sodium has emerged as a prospective sustainable alternative,
but so far organosodium reagents have made limited impact
due to their low solubility in hydrocarbon solvents and their
(over)high reactivity, precluding their use in ethereal
solvents and limiting the functional group compatibility.
This Minireview has highlighted selected recent advances
that have been reported to mitigate some of these impediments. For example, careful choice of Lewis donors can
disaggregate and solubilise these reagents, the use of flow
set-up designs allows for functionalisation of more fragile
substrates and the use sodium dispersions has enabled access
to a wide range of sodium aryl complexes which can be
subsequently efficiently employed in C C bond forming
processes. Overall, it is possible to run organosodium
chemistry either under homogeneous or heterogeneous
conditions, e.g., by making use of the appropriate Lewis
donors in conventional solvents or by operating without any
ligand on the oil-water/DES interface, respectively. It is
worth stressing as well that the higher reactivity that is
present with these compounds, sometimes seen as a
limitation, can actually be advantageous in the development
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of new reactivity that is not possible with organolithium
compounds, reaching even catalytic transformations, normally more typical for transition metals. For this purpose,
the study of the reactive intermediates and the understanding of their constitution have proven to be valuable for
advancing this field. We believe that this is just the tip of the
iceberg, and we expect that innovations on the use and
understanding of organosodium chemistry will keep growing, and which will allow the chemistry community to fully
exploit the potential of these reagents in organic synthesis.
Acknowledgements
We thank the Swiss National Science Foundation (SNSF)
(projects numbers 210608 and 188573) for its generous
sponsorship, which includes the award of a SNSF Swiss
Postdoctoral Fellowship to Andreu Tortajada. Our sincere
thanks also go to past and present co-workers from the
Hevia laboratory for their invaluable intellectual and
experimental contributions in advancing of organosodium
chemistry as well as to Professor Robert Mulvey (University
of Strathclyde) for his mentorship to EH and valuable
comments. Open Access funding provided by Universität
Bern.
Conflict of Interest
The authors declare no conflict of interest.
Data Availability Statement
Data sharing is not applicable to this article as no new data
were created or analyzed in this study.
Keywords: Alkali Metals · Metalation · Organometallic ·
Sodium · Sustainability
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Manuscript received: September 12, 2023
Accepted manuscript online: October 6, 2023
Version of record online: ■■■, ■■■■
© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH
15213773, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/anie.202313556 by Cochrane Canada Provision, Wiley Online Library on [24/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Minireviews
Angewandte
Chemie
Minireviews
Alkali Metals
D. E. Anderson, A. Tortajada,*
E. Hevia*
e202313556
New Frontiers in Organosodium Chemistry
as Sustainable Alternatives to Organolithium Reagents
Angew. Chem. Int. Ed. 2023, e202313556
With demand for lithium soaring due to
its escalating use in energy applications,
the heavier organosodium compounds
have started to be considered as alternatives in synthesis. Recent reports have
tackled their solubility problems, tamed
their high reactivity and studied their
intermediates constitution, accessing
now transformations that were not possible with organolithiums, and opening
new vistas for the use of these organosodium reagents.
© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH
15213773, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/anie.202313556 by Cochrane Canada Provision, Wiley Online Library on [24/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Minireviews