On the dichotomic reactivity of lithiated styrene oxide: A computational and multinuclear magnetic resonance investigation

Article abstract of DOI:10.1002/chem.200900834

A multinuclear magnetic resonance investigation, supported by density functional theory calculations, has been synergically used to investigate the configurational stability, reactivity and aggregation states of a-lithiated styrene oxide in THF at 173 K.

Full text of DOI:10.1002/chem.200900834

DOI: 10.1002/chem.200900834
On the Dichotomic Reactivity of Lithiated Styrene Oxide: A Computational
and Multinuclear Magnetic Resonance Investigation
Vito Capriati,*[a] Saverio Florio,*[a] Filippo Maria Perna,[a] Antonio Salomone,[a]
Alessandro Abbotto,[b] Mohamed Amedjkouh,[c] and Sten O. Nilsson Lill[c]
Dedicated to the Centenary of the Italian Chemical Society
Abstract: A multinuclear magnetic res-
onance investigation, supported by
density functional theory calculations,
has been synergically used to investi-
gate the configurational stability, reac-
tivity and aggregation states of a-lithi-
ated styrene oxide in THF at 173 K.
ly broken in some stereoisomers re-
duces their symmetry and complicates
the NMR spectra: two diastereoiso-
mers each having a pair of diastereo-
topic carbon atoms slowly inverting at
the lithium atom in absence of tetrame-
thylethylenediamine (TMEDA) have
been detected. A (13C,7Li)-HMQC ex-
From natural bond analysis, the mono-
meric aggregate was proven to have a
lower carbenoid character with respect
to bridged O-coordinated dimeric ag-
gregates. The employment of suitable
experimental conditions in terms of
concentration, temperature and the
presence or not of TMEDA are crucial
to mitigate at the best the “carbene-
like” reactivity of lithiated styrene
NMR
[a,b-13C2]styrene oxide (also in an
enantiomerically enriched form)
studies
on
a-lithiated
7
periment to correlate Li and 13C reso-
nances of the various aggregates has
been performed for the first time.
À
proved that in THF this oxiranyllithi-
um is mainly present as a solvated
monomeric species in equilibrium with
a complex mixture of stereoisomeric
dimeric aggregates, as well as with
bridged and tetrameric aggregates. The
oxide toward intermolecular C Li in-
sertions, eliminative dimerisation reac-
tions and ring-opening reactions. A
two-step mechanism for the deprotona-
tion of styrene oxide by sBuLi in THF
has been proposed and discussed as
well as competitive side reactions.
Keywords: carbenoids
·
density
functional calculations · lithiation ·
NMR spectroscopy · oxygen hetero-
cycles
À
fact that some Ca Li bonds are partial-
[a] Prof. Dr. V. Capriati, Prof. Dr. S. Florio, Dr. F. M. Perna,
Dr. A. Salomone
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900834. It contains total ener-
Dipartimento Farmaco-Chimico, Universitꢀ di Bari
Consorzio Interuniversitario Nazionale Metodologie e
Processi Innovativi di Sintesi C.I.N.M.P.I.S.
Via E. Orabona 4, 70125 Bari (Italy)
Fax : (+39)080-5442231
gies (atomic units) (B3LYP/6-31+G(d) and B3LYP/6-311+GACHTUNGTRENNUNG(d,p))
and Cartesian coordinates (B3LYP/6-31+G(d)) of neutral and lithiat-
ed styrene oxide (S3–S15); natural charge distribution analysis in neu-
tral styrene oxide (S16); natural charge distribution analysis in free
(2a) and solvated lithium styrene oxide (S17); comparison of selected
geometrical parameters in free (2a, 4a and 4c) and solvated lithium
salt (S18); natural charge distribution analysis in free and solvated
dimer (4c) of lithium styrene oxide (S19); comparison of the theoreti-
cal and experimental 13C NMR shieldings for neutral styrene oxide 1
(S20); theoretical 13C NMR shieldings in free dimers (4) and solvated
lithium salt (S20); natural bond orbital energies of sOÀCa and s*OÀCa
orbitals in neutral and lithiated styrene oxide in different aggregates
and solvated forms (S20); optimised structures for neutral 1 and side
views of 4a–4d (S21–S23); 1D and 2D NMR spectra (S23–S27); sche-
matic drawings of additional aggregates (S27).
E-mail: capriati@farmchim.uniba.it
florio@farmchim.uniba.it
[b] Prof. Dr. A. Abbotto
Dipartimento di Scienza dei Materiali
Universitꢀ di Milano-Bicocca
Via Cozzi 53, 20125 Milano (Italy)
[c] Prof. Dr. M. Amedjkouh, Dr. S. O. Nilsson Lill
Department of Chemistry
University of Gothenburg
412 96, Gçteborg (Sweden)
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FULL PAPER
Introduction
Oxiranyllithium species are an amazing class of reactive in-
termediates, which today have been playing more and more
a leading role in stereoselective organic synthesis.[1] Since a
direct lithiation of terminal epoxides can be successfully per-
formed in absence of electron-withdrawing groups,[2] this
suggests that this kind of a-oxygen-substituted organolithi-
um species have an “intrinsic stability”, presumably due
either to the fact that oxygen substitution increases thermo-
dynamic carbanion stability[3] or that their b-eliminative de-
composition (being the reverse of a 3-endo-trig cyclisation)
may be disallowed according to the Baldwinꢂs rules.[4] Their
ring-opening reactions are, indeed, mainly dominated by al-
kylative deoxygenations (especially when organolithium spe-
cies are used as lithiating agents),[1a,c,f,g,j,5a–c] “homocoupling”
reactions,[1g,5d] selective isomerisations (e.g., with medium-
sized cycloalkene oxides),[1a,c,f,j,6] 1,2-H (alkyl, aryl)
shifts,[1a,c,f,j] all referable to the well-known carbenoid na-
ture[1f,7] of these reactive intermediates. However, despite
the growingly application in stereoselective synthesis of oxir-
anyllithium species,[1d,h–j,8] their structural features remain a
matter of interpretation. Many questions are still unan-
swered, such as the role played by the so-called “stabilizing”
substituents: do they simply enhance the acidity of the adja-
Scheme 1. Deprotonation of styrene oxide 1 and quenching of anions 2
and 3 with electrophiles.
if a longer reaction time (particularly in the case of lithiated
styrene oxide), a higher temperature or a nondonor solvent
are employed, their carbenoid character[17] comes into play.
Now, the questions are: how strong is this carbenoid char-
acter in ethereal solvents? What are the factors responsible
for such a “carbene-like” reactivity? Is the “same species”
able to exhibit an ambiphilic behaviour according to the em-
ployed experimental conditions or could “different species”
be involved instead? In this paper, we will deal with the so-
lution structure and the nature of lithiated styrene oxide 2
as well as the role played by the phenyl group, the base, the
solvent, the temperature and the ligand (TMEDA) on its
formation and “stabilisation”. Computational studies sup-
porting multinuclear magnetic resonance investigations have
been carried out with the aim of furnishing a plausible ex-
planation about the “factors” responsible for the two facets
of the reactivity of this lithiated species: the carbanionic or
the carbenoid character.
À
cent C H epoxide bond or are they really able to delocalise
the incipient negative charge formed upon deprotonation?[9]
And, if this is the case, how could configurational stability
sometimes be observed? Since the factors affecting their re-
activity and related mechanisms are not well understood, it
is of crucial importance to study their solution structure for
the optimisation of their coupling reactions with electro-
philes. So far, only a few detailed rate studies of LiTMP-
and LDA-mediated (LiTMP=lithium tetramethylpiperi-
dide; LDA=lithium diisopropylamide) lithiation of epox-
ides have been reported by Collumꢂs group.[10] The structure,
configurational stability and stereodynamics in solution of
a-lithiated 3,3-dimethyl-2-oxazolinyloxirane have recently
been investigated by our group by means of in situ IR and
NMR spectroscopy.[11] Interestingly, oxiranyl anion method-
ology has also recently been applied to preparative scale
synthesis of substituted epoxides by taking advantage of mi-
croflow systems, which also served as a powerful tool for
mechanistic studies.[12] Our concerns in the oxiranyllithium
field, aimed at making more functionalised epoxides,[1d,g,j13]
led us to the observation that lithiated styrene oxide[14] 2,
among other oxiranyllithium species, could be generated by
treating its precursor 1 with sBuLi/tetramethylethylenedia-
mine (TMEDA) in THF and successfully and stereospecifi-
cally trapped with electrophiles to give more substituted sty-
rene oxides with retention of configuration at the benzylic
carbon atom (Scheme 1). Likewise, highly stereospecific
were the coupling reactions with electrophiles of lithiated
trans- and cis-3-methyl-2-phenyloxiranes[15] 3, which also ex-
hibited a higher thermal stability (Scheme 1).[16] This is an
indication of a carbanionic behaviour exhibited by such re-
active intermediates at low temperature in THF. In contrast,
Results and Discussion
Computational studies: First of all, to gain further insights
about the nature and the reactivity of this lithiated system, a
computational investigation at the B3LYP/6-31+G(d) level
of theory on neutral 1 and lithiated styrene oxide 2 was un-
dertaken.[18,19] The natural charge analysis[20] on the neutral
styrene oxide 1 shows that charges on phenyl and oxirane
ring are almost neutral (see Figure S1 and Table S1 in the
Supporting Information).
Free lithium salt: In the free lithium salt (Figure 1), the lithi-
um ion has a +0.91 positive charge, counterbalanced by a
À0.91 negative charge on the organic anionic system. How-
ever, the negative charge is slightly delocalised onto the
phenyl ring, being mostly resident on the oxirane ring
(À0.77; Table S2 in the Supporting Information). This is
likely the consequence of the sp3-like nature of the depro-
tonated carbon atom, with low overlap with the phenyl p
system. Computed bond-lengths and p charges support this
conclusion (Table S3 in the Supporting Information). The
total phenyl p charge is increased by only 55 me upon de-
protonation. It should be noted that, in line with the litera-
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V. Capriati, S. Florio et al.
Supporting Information). A total rearrangement of the elec-
tron structure takes place upon solvation that matches the
geometric structural rearrangement (vide infra). Depending
on the computed species, coordination between lithium and
the oxirane oxygen may be either present or absent. As de-
rived from bond lengths (Figure 1 and Table S3 in the Sup-
porting Information), this interaction is present in the free
and di-solvated species, but is no longer maintained when a
third molecule of solvent is introduced. It should be noted
that, either by coordination with oxirane oxygen or solvent
molecules, the lithium ion reaches the tetracoordination
both in the di- and tri-solvated salt. Similar behaviour was
shown for the coordination of lithium enolates by ethereal
solvents.[23] Bond lengths for solvated compounds compare
well those previously found for lithium enolates as well.[23,24]
Solvation energies: As expected, the solvation energy strong-
ly decreases from the first two solvations to the third one
(Scheme 2). Whereas in the first two steps the average
Scheme 2. Dimerisation and solvation energies (in kcalmolÀ1) calculated
using B3LYP/6-311+GACTHNUTRGNE(UNG d,p). Numbers refer to relative energy values
with respect to the reference chemical species 22a+6THF. 4c indicates
the most stable dimeric aggregate (Figure 3).
energy per solvation is À17.0 kcalmolÀ1, in the last step the
energy is as little as À5.6 kcalmolÀ1. This behaviour is the
consequence of the saturation of the binding energies as the
number of solvent molecules increases and is consistent with
data reported in the literature for the solvation of the lithi-
um cation,[25] methyllithium,[26] lithium amides,[27] and lithi-
um enolates.[23,24] The binding energy of the third molecule
of solvent is small but still important, considering the simul-
taneous loss of the interaction between the counterion and
the oxirane oxygen. Therefore, the coordination with a third
molecule of THF provides the system with a greater stability
than that originating from the interaction with the oxirane
ring. However, it should be considered that the solvation
process is entropically unfavoured, since it reduces the free-
Figure 1. B3LYP/6-31+G(d) optimised structures of free (2a; top), di-
([2a(thf)2]; middle) and tri-solvated ([2a(thf)3]; bottom) lithiated styrene
oxide 2.
G
ACHTUNGTRENNUNG
ture, the p charge on the ipso-carbon atom, directly linked
to the carbanionic site, is positive.[21]
Solvated lithium salt: Lithium coordination by two or three
molecules of THF increases the negative charge delocalised
onto the phenyl ring from 16% (free species) to 25% in the
tri-solvated system.[22] Accordingly, the p charge increases to
À0.10 in the tri-solvated species from À0.05 in unsolvated
2a. It is important to note that the increase of negative
charge in the phenyl ring upon solvation is not simply due
to the electron-donor properties of the solvent molecules,
since the global negative charge increase of the lithium salt
is smaller than that of the phenyl portion (Table S2 in the
7
dom of motion. From literature data based on 13C and Li
NMR studies on THF-solvated alkyllithium species,[28]
a
contribution of about 5–10 eu per molecule of solvent can
be extrapolated. At 173 K the entropic contribution of the
third solvation step would at the most be approximately
2 kcalmolÀ1, which is smaller than the energy gain, leading
to a still negative DG value.
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We can, therefore, conclude that the tri-solvated species,
with no coordination between Li and the oxirane ring
oxygen and with an almost tetrahedral arrangement around
the carbanionic carbon, is the most stable species both on
the basis of energy (DE) and Gibbsꢂ energy (DG) data.
Free lithium dimer: Because of the high ionic character[29] of
À
the Li C bond in lithiated styrene oxide, dipole–dipole at-
traction results in the formation of supermolecular aggre-
gates.[24] The balance between enthalpy gain in the forma-
tion of new bonds and entropy loss discriminates between
solvation and aggregation. Four different bridged dimers
(4a–4d) of lithiated styrene oxide were investigated
(Figure 2).
The energy difference among all four isomers is about
1 kcalmolÀ1, which indicates a possible equilibrating multi-
tude of species simultaneously present. In the most stable
isomer (4a), the lithium ion coordinates the oxirane oxygen
and to two Ca atoms, one in each monomeric unit
(Figure 2). This means that each Ca-carbon coordinates two
lithium ions. The lithium atoms, oxirane oxygen atoms, and
the Ca atoms form a nearly planar six-membered ring with
the Cb atoms positioned on each side of this plane (see Sup-
porting Information for side views, Figures S2–S5). The di-
merisation does not affect the total delocalisation of nega-
tive charge into the phenyl ring of 4a, which remains at
15%.[30] This contrasts the observation of the role of solva-
tion, in which an enhanced delocalisation into the phenyl
ring resulted. The reaction energy for the formation of
dimer 4a from two monomers of 2a is À45.4 kcalmolÀ1 at
the B3LYP/6-311+GACTHNUTRGNEUNG
(d,p)[31] level of theory. Thus, in a non-
coordinating solvent as toluene, lithiated styrene oxide
would appear as a dimer (or possibly a larger aggregate).
However, accounting for the solvation energy from six THF
molecules on two molecules of 2a (in total À79.2 kcal
molÀ1), indicates that the solvation will break the aggregate
of lithiated styrene oxide into solvated monomers
(Scheme 2). Can solvation of the dimer make a shift in this
equilibrium?
Solvated lithium dimer: Upon solvation of the different di-
meric isomers, it is found that di-solvated [4cACTHNUGTRENUNG(thf)2] is the
most stable (Figure 3). The energy difference between the
different isomers is now increased to up to 3 kcalmolÀ1. In a
fully equilibrated solution of lithiated styrene oxide in THF
at low temperature, this isomer of the dimer will be mainly
observed. At elevated temperatures, it is more likely that a
multitude of isomers are present. The solvation energy for
solvation of isomer 4c with two molecules of THF is found
to be À29.2 kcalmolÀ1. This solvation energy is somewhat
smaller than that observed for the monomer, but it clearly
compensates for the loss of translational entropy from the
two solvent molecules. From these results, we can conclude
that isomer 4c will be explicitly solvated. When comparing
Figure 2. Optimised structures of the free lithiated dimers 4a–4d of sty-
rene oxide and relative energies (kcalmolÀ1).
loss of entropy, in this comparison for three molecules at
173 K, it is most probable that the state including the dimer
is the most preferred. The small energy difference and the
accuracy of the method does not allow us to clearly distin-
guish which one of the two states that will be most populat-
the energies for [4cACHTNUTRGENN(UG thf)2] and [2aACHTUNGTRNEN(GUN thf)3], we find that the
tri-solvated monomer is 4.6 kcalmolÀ1 more stable than the
di-solvated dimer (Scheme 2). Taking into the account the
ed. The main structural features of isomer [4cACTHNUGTRENUNG(thf)2] are
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V. Capriati, S. Florio et al.
In conclusion, the structure
and energy analysis indicate
that in THF, lithiated styrene
oxide may be present as a di-
solvated dimer or as a tri-sol-
vated monomer. In light of the
small energy difference be-
tween the two most stable
states, could we provide some
more information to put into
the two different scales of the
balance and be able to decide
on the nature and aggregation
state of lithiated styrene oxide?
To this end, we found it instruc-
tive to perform an NMR study.
1
7
6
13C, H, Li and Li NMR spec-
troscopic studies—deprotona-
tion of styrene oxide in the
presence of TMEDA
7
1H, 13C and Li NMR investiga-
tion in [D8]THF at 173 K:
NMR has proven to be power-
ful for studying the structure,
bonding and dynamics of orga-
nolithium compounds in solu-
tion.[33] Lithiated styrene oxide
is a very reactive intermediate
and NMR experiments have
shown that it is kinetically
stable in [D8]THF in the pres-
ence or absence of TMEDA
over a period of a few hours
only if the temperature is rigor-
ously kept at a value not higher
Figure 3. Optimised structures of the di-solvated lithiated dimers ([4aACTHNUTRGNEN(UG thf)2]–[4dACHUTTGNREN(NUNG thf)2]) of styrene oxide and
relative energies (kcalmolÀ1).
intact when THF is coordinated, although a minor elonga-
than 175 K. Lithiation of styrene oxide was performed with
sBuLi.
À
À
tion of the Li O and Li Ca bonds are observed (Figure 3
and Tables S3 and S4 in the Supporting Information). It is
interesting to observe the structural features of some other
This organolithium was found by Fraenkel to be a mixture
of diastereomeric dimers, tetramers and hexamers that
invert slowly at the lithiated carbon in cyclopentane (2m,
232 K),[34] whereas in THF (1.2m, 177 K) Bauer detected
two sets of signals consistent with a monomer–dimer equi-
librium.[35] A 0.2m solution of sBuLi in [D8]THF at 173 K
showed only one set of 13C NMR signals for the anionic spe-
cies, the chemical shifts of which (d=39.7, 28.8, 19.4 ppm
for the C-3, C-1 and C-4 carbon atoms, respectively) result-
ed to be very close to those reported by Bauer for the mon-
omeric aggregate (Figure 4a).[35] The anionic carbon (C-2)
was hidden under [D7]THF at d=25.7 ppm, as observed
from a 2D 1H,13C-HSQC-DEPT experiment (Figure S8 in
the Supporting Information).
isomers studied ([4a
Figure 3). For example, one of the Ca Li bonds in the
isomer [4b(thf)2] is partially broken; in fact, a Ca-Li distance
of 2.70 ꢃ can be viewed as only a partial interaction. As a
ACHTUGNTRENGNU(N thf)2], [4bACHTUNTREGN(GNUN thf)2] and [4dCATHNUGTREN(NUGN thf)2],
À
ACHTUNGTRENNUNG
fourth example, [4dACTHNUTRGNEUNG(thf)2] has two partially broken bonds
with distances of about 2.5 ꢃ.[32]
The analysis of the solvated dimers 4 indicates that solva-
tion increases the delocalisation of negative charge. In
isomer [4cACHTUNGTRENNUNG(thf)2] about 20% of negative charge is located in
the phenyl rings (Table S4 in the Supporting Information),
similarly as that observed for the solvated monomer 2a.
What contrasts the delocalisation in the solvated monomer
and the solvated dimer is that, for the monomer, negative
charge is taken about equally from the oxirane oxygen and
the Ca carbon atoms, while in the dimer most of the nega-
tive charge is taken from the Ca carbon atom.
By adding a preformed mixture of styrene oxide (1 equiv)
and TMEDA (1 equiv) in [D8]THF to a precooled solution
(173 K) of sBuLi (1.2 equiv) in [D8]THF (0.2m, see Experi-
mental Section), a new set of signals slowly emerged in both
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Figure 5. a) Partial 1H NMR spectrum of 0.2m sBuLi in [D8]THF at
173 K. b) Partial 1H NMR spectrum of 0.2m sBuLi/sBuOLi (0.5:1 O:Li
ratio) in [D8]THF at 173 K. c) Partial 1H NMR spectrum of 0.2m sBuLi
in [D8]THF at 173 K with one equivalent of TMEDA. d) 1H NMR spec-
trum of 0.2m 2 in [D8]THF at 173 K with one equivalent of TMEDA at
Figure 4. a) 13C NMR spectrum of 0.2m sBuLi in [D8]THF at 173 K. b)
13C NMR spectrum of 0.2m 2 in [D8]THF at 173 K with one equivalent of
TMEDA at the beginning of lithiation. c) DEPT-135 NMR spectrum of
0.2m 2 in [D8]THF at 173 K with one equivalent of TMEDA at the end
of lithiation. d) 13C NMR spectrum of 0.2m sBuLi in [D8]THF at 173 K
with one equivalent of TMEDA. e) 7Li NMR spectrum of 0.2m 2 in
[D8]THF at 173 K with one equivalent of TMEDA at the end of lithia-
tion. An asterisk indicates an oxygen-derived impurity. Cy, b and s stand
for cyclohexane, butane and starting styrene oxide, respectively. All spec-
tra were measured at natural abundance lithium and carbon.
1
the beginning of lithiation. e) H NMR spectrum of 0.2m 2 in [D8]THF at
173 K with one equivalent of TMEDA at the end of lithiation. f) 7Li
NMR spectrum of 0.2m sBuLi in [D8]THF at 173 K. An asterisk indicates
alkoxides/mixed aggregates with sBuLi. Cy, b and s stand for cyclohex-
ane, butane and starting styrene oxide, respectively. All spectra were
measured at natural abundance lithium and carbon.
carbon atoms, each signal showed also a shoulder. More-
over, the 1H,13C-HSQC-DEPT spectrum showed that the
two lowest field broad proton singlets at d=6.58 and
6.91 ppm (relative ratio 1:4, Figure 5d,e) correlate with only
three cross-peaks with the corresponding aromatic carbon
atoms (Figure S9 in the Supporting Information) so testify-
ing an almost chemical shift isochronicity for meta- and
ortho-aromatic protons. This finding is consistent with a ring
rotation still fast on the NMR timescale at 173 K. The slight
upfield shifts exhibited by ortho- and para-aromatic carbon
atoms further to lithiation was in agreement with a negligi-
ble delocalisation of the p charge onto the phenyl ring, as
suggested by DFT calculations (vide supra). In addition, the
13C signal of the a-lithiated carbon appeared as a very broad
singlet between 81.0–83.0 ppm not revealing any line split-
1
the 13C (Figure 4b) and H (Figure 5d) NMR spectra in the
presence of both starting oxirane and “unreacted” sBuLi,
the latter mainly present as a monomeric aggregate (vide
supra). With time, the starting epoxide completely disap-
peared (Figures 4c, 5e). The new set of signals could be
clearly ascribed to lithiated styrene oxide, either because
several preparations were fully reproducible or because
after “quenching” at low temperature with CH3OD in the
NMR tube the only species detected resulted to be a-deu-
terated styrene oxide (>98% D). As demonstrated by
DEPT-135 (Figure 4c) and phase-sensitive heterocorrelation
1H,13C-HSQC-DEPT experiments (Figure S9 in the Support-
ing Information), the signals in the range 163.0–119.0 ppm
(d=162.4, 127.5, 122.2 and 119.7 ppm, Figure 4b,c) could
only be assigned to the aromatic carbon atoms of lithiated
styrene oxide; in the case of the ortho-, para- and ipso-
7
ting because of Li coupling (Figure 4b).
At the earliest stage of deprotonation reaction, only two
small broad oxiranyl CH peaks of the anion could be detect-
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V. Capriati, S. Florio et al.
1
ed in the H NMR spectrum at d=2.84 and 3.00 ppm (Fig-
tensities (Figure 5b). However, no further attempts were
made to elucidate the solution structure of the above aggre-
gates.[40] Running a 13C NMR spectrum of a 1:1 mixture
sBuLi/TMEDA in THF (0.2m), the TMEDA CH2 resonance
fell to d=58.1 ppm at 173 K (Figure 4d) and in the
1H NMR spectrum a new broad singlet appeared below 0 at
À1.21 ppm flanking the main one at À0.95 corresponding to
“free” sBuLi (Figure 5c). The new upfield shift of the sBuLi
a-methine proton may be the consequence of an increase of
the negative charge on the carbanion, because of the com-
plexation of the lithium by the diamine, as similarly report-
ed.[41] Therefore, it seems as though a low TMEDA concen-
tration is able to compete with bulk THF for coordination
sites on lithium of sBuLi. Once styrene oxide starts to be de-
protonated with such a 1:1 mixture sBuLi/TMEDA in THF,
as the lithiation progresses, the TMEDA CH2 resonance
broadens considerably and moves downfield by about
ure 5d). As the reaction progresses, other small peaks ap-
peared between 6.00 and 7.50 ppm (aromatic region) flank-
ing the main ones at d=6.58 and 6.91 ppm as well as be-
tween 2.80 and 3.20 ppm (CH2 region; Figure 5e). Similarly,
7
the Li NMR spectrum (Figure 4e) exhibited, besides a very
broad signal centred at d=1.57 ppm relative to sBuLi, up to
seven peaks (d=0.01, 0.19, 0.50 0.57, 0.61, 0.80 and
1.32 ppm) representative of several nonequivalent lithium
species; peaks at d=0.50 and 0.57 ppm being most probably
associated with alkoxides/mixed aggregates (vide infra and
Figure 5 f). These findings suggest that several differently
aggregated species seem to coexist at this temperature and
concentration in solution. The resonance of b-CH2 oxiranyl
carbon atom could only be indirectly detected by means of
a H,13C-HSQC-DEPT experiment, because it was hidden by
1
the CH2 groups of TMEDA at d=58.7 ppm. In fact, this
broad 13C signal gave H correlations with some CH2 peaks
0.5 ppm to d=58.7 ppm (Figure 4b). In the H NMR spec-
1
1
present at the end of deprotonation reaction; in particular,
with that at d=3.00 ppm (Figure 5e and Figure S10 in the
Supporting Information).[36]
trum, a new broad peak shifted to higher field forms at d=
À1.29 ppm at the expense of the previous one at d=
À1.21 ppm, the former being also flanked by two small and
broad peaks at d=À1.19 and À1.43 ppm (Figure 5d). At the
end of the deprotonation reaction, in the 13C NMR spec-
trum, the TMEDA CH2 resonance once again moves upfield
Running different experiments with 0.8 and 1.8 equiva-
lents of sBuLi, the resulting spectra were identical (apart
from additional signals deriving from excess neutral styrene
oxide or excess organolithium), suggesting that no heteroag-
gregates between lithiated styrene oxide and organolithium
occurred.[37] Therefore, the “role” of sBuLi, coexisting with
both the substrate and the lithiated epoxide throughout the
deprotonation reaction, was investigated.
1
to d=58.1 ppm (Figure 4c) and, in the H NMR spectrum,
the peak at d=À1.29 ppm increases its intensity, whereas
that at d=À1.43 ppm disappears (Figure 5e). The above
scenario always recurs each time styrene oxide is deproton-
ated with an excess sBuLi in the presence of TMEDA.
However, it was not established whether the disappearance
of the peak at d=À1.43 ppm was due to a competitive reac-
tion of one of the sBuLi/sBuOLi aggregates with the epox-
ide or rather to the slow and reversible formation of an ep-
oxide–alkyllithium complex, which undergoes deprotona-
tion. Most likely, the peak at d=À1.29 ppm, the intensity of
which increases with time, may be related to the complex
between lithiated epoxide and sBuLi; in fact, performing
the lithiation with a sub-stoichiometric amount of sBuLi in
the presence of TMEDA both the peaks at d=À0.95 and
À1.29 ppm are absent. On the other hand, the broadening
and the shifting that the TMEDA CH2 resonance undergoes
during the course of lithiation supports the hypothesis that a
dynamic exchange between the complex sBuLi/TMEDA
with both neutral and lithiated styrene oxide may be really
underway. NMR studies of organolithium–epoxide com-
plexes reported in the literature[42] have provided evidence
for the tendency of epoxide oxygen atom to lithium coordi-
Formation of mixed alkoxides aggregates and organolithium–
1
epoxide complexes: The H NMR spectrum of 0.2m sBuLi in
[D8]THF at 173 K showed three more minor broad peaks
shifted to higher field at d=À1.19, À1.33 and À1.43 (Fig-
ure 5a) in the region below 0 ppm (which is that corre-
sponding to protons attached to the alkyllithium carbanionic
carbon), apart from one main signal at À0.95 ppm, which
was assigned to the proton attached to C-2 carbon of sBuLi
(from 1H,13C-HSQC-DEPT shift correlation, Figure S8 in
7
the Supporting Information). Similarly, Li NMR spectrum
showed in addition to the peak at d=1.48 ppm correspond-
ing to free sBuLi, three more peaks shifted to higher field at
d=0.68, 0.57 and 0.50 ppm (Figure 5 f). As the presence of
molecular oxygen in the solvent may lead to the formation
of alkoxides, we wondered whether the aforementioned
peaks might be due to mixed alkoxide complexes. Indeed, it
has been reported that lithium alkoxides formed in less than
stoichiometric amounts from alkyllithium compounds can
produce mixed alkyllithium/lithium alkoxides aggrega-
tes.[28b,38,39] To check the formation of possible mixed aggre-
gates between sBuLi and sBuOLi, the synthesis of sBuOLi
was accomplished by reacting a 0.2m solution of sBuLi in
THF with 2-butanol, the latter employed in less than stoi-
chiometric amount (0.5:1 O/Li ratio). The 1H NMR spec-
trum for this sample contained the same peaks seen in the
0.2m solution of sBuLi in THF (that is, at d=À0.95, À1.19,
À1.33 and À1.43 ppm), although with slightly different in-
nation. That
a
complex-induced proximity effect
(CIPE)[43a–d] may be playing a role in the course of lithiation
of styrene oxide seems reasonable, also considering the com-
petition occurring between a- and b-deprotonation (vide
infra). Recently, the regioselective (a- vs. ortho) lithiation of
N-alkylarylaziridines has similarly been rationalised on the
basis of a CIPE effect, which would operate jointly with
stereodynamics occurring at the aziridine nitrogen.[43e] To
date, such pre-lithiation complexes have been barely ob-
served spectroscopically.[44] To get more information about
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Carbenoid Chemistry
FULL PAPER
the solution structure of this lithiated epoxide, we synthes-
ised a doubly 13C-enriched styrene oxide on the epoxide
ring.
mixture of a monomeric contact ion pair (CIP). The comple-
mentary 13C,13C coupling constant value was found for the
ACTHNUTRGNEUNG
CH2 signal at d=58.6 ppm (1J(13C,13C)=11 Hz). This fact is
consistent with a close connection of the above carbon
atoms within the same aggregate. In nonlithiated doubly
13C-enriched styrene oxide the 13C,13C coupling constant
value between the two oxirane-ring carbon atoms is 28 Hz;
therefore, there has been a decrease in the constant further
1
7
6
13C, H, Li and Li NMR spectroscopic studies—deprotona-
tion of [a,b-13C2]styrene oxide
13C NMR
investigation
in
[D8]THF
at
173 K:
[a,b-13C2]Styrene oxide was synthesised in 76% yield by ep-
oxidation of the corresponding [a,b-13C2]styrene (see Exper-
imental Section). When a mixture of one equivalent of this
doubly 13C enriched epoxide and one equivalent of TMEDA
in [D8]THF was treated at 173 K with 0.8 equivalents of
sBuLi (0.2m being the resulting solution), new sets of signals
in the range 57.0–93.0 ppm were now clearly detected in the
13C NMR spectrum (Figure 6). DEPT-135 analysis revealed
to lithiation (DJACHTUNGTRENNUNG
coupling constant between the ipso and the a-carbon also
decreased on lithiation from 57 to 27 Hz (Figure 6).
An analogous trend was found by Seebach[45] in some
lithiated organohalides for the coupling constants between
carbenoid C atoms and 13C nuclei directly attached to them;
this fact has been interpreted as the consequence of a re-
duced degree of hybridisation of such lithiated carbon
atoms.
Over the range 119–140 ppm, two doublets associated
with two CH carbon atoms (from DEPT-135 analysis),
strongly coupled to each other by means of their 13C nuclei
ACTHNUTRGNEUNG
(1J(13C,13C)=72 Hz), were noted at d=129.7 and 136.2 ppm
(Figure 6). They were assigned to the two vinylic CH carbon
atoms of the trans-alkene 3-methyl-1-phenyl-pent-1-ene 5
(Figure 7).[46] This kind of alkene was previously observed
1
Figure 7. a) and b) refer to 13C{1H} and H-13C full-coupled NMR spectra,
respectively, of 0.2m lithiated [a,b-13C2]styrene oxide in [D8]THF with
one equivalent of TMEDA after warming up to room temperature from
173 K.
Figure 6. 13C NMR spectrum of 0.2m lithiated [a,b-13C2]styrene oxide in
[D8]THF at 173 K with one equivalent of TMEDA. s and o, m, p stand
for starting [a,b-13C2]styrene oxide and ortho-, meta- and para-carbon
atoms of lithiated [a,b-13C2]styrene oxide, respectively. An asterisk indi-
cates a CH vinylic carbon.
by our group studying the “alkylative reduction” of lithiated
styrene oxide promoted by sBuLi[14] and by Mioskowski (see
also Scheme 8).[47,48] Interestingly, by warming up a solution
of such an anion in the presence of an excess sBuLi sudden-
ly to room temperature, another pair of two doublets flank-
ing the previous ones appeared at d=153.7 and 109.1 ppm
the presence of at least four chemically nonequivalent CH2
groups (d=58.1, 58.5, 59.1, and 60.3 ppm), one CH signal at
d=61.2 ppm, six broad signals assignable to quaternary
carbon atoms (d=73.1, 73.7, 74.7, 81.6, 82.6, and 83.7 ppm)
and another small CH peak at d=92.6 ppm (vide infra).
Above all, most diagnostic was the signal at d=81.6 ppm,
which exhibited a broad 1:1:1:1 quartet (7Li I=3/2) typical
ACTHNUTRGNEUNG
(1J(13C,13C)=72 Hz, Figure 7a). The corresponding 1H,13C
fully coupled spectrum (Figure 7b) revealed that they corre-
spond to two vinylic carbon atoms: a quaternary carbon
(d=153.7 ppm, d, 1J
(13C,13C)=72 Hz) and a CH2 carbon
ACHTUNGTRENNUNG
ACTHNGUTRENNUG CAHTUNGTRENNUNG
of a carbon coupled to only one lithium atom (1J
34 Hz), each line being further poorly split into a doublet
because of a 13C,13C coupling (1J(13C,13C)=11 Hz; Figure 6);
it may be presumably indicating the presence in the reaction
A
(d=109.1 ppm, td, 1J(13C,1H)=156 Hz, 1J(13C,13C)=72 Hz);
they were assigned to the alkene 3-methyl-2-phenyl-pent-1-
ene (6; Figure 7, see also Scheme 8).[14,47] A 2D 13C,13C
COSY experiment confirmed that the two pairs of doublets
AHCTUNGTRENNUNG
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7965

V. Capriati, S. Florio et al.
refer to 13C nuclei scalar coupled to each other within two
different alkenes (Figure S11 in the Supporting Informa-
tion). The above regioisomeric alkenes may derive from a
59.2 ppm), and another broad singlet at d=60.3 ppm. A
ACTHNUTRGNEUNG
triple-resonance experiment, 13C{1H,7Li}, was run on the
same sample; the residual coupling constants still present in
the spectrum for the various peaks now being referable to
13C,13C couplings only (Figure 8d). Under this double decou-
pling, the previous broad quartet at d=81.2 ppm became a
À
stereospecific intermolecular alkylative insertion into C Li
bonds of the corresponding carbenoid intermediates further
to both a- and b-proton abstraction promoted by sBuLi, as
reported[47] (vide infra).
ACTHNUTRGNEUNG
narrow doublet (1J(13C,13C)=11 Hz), the broad peak at d=
81.8 ppm resolved into two doublets of equal intensity at
1
Interaction with TMEDA: A 0.2m sample of 2 without
TMEDA was prepared and a 13C{1H} NMR spectrum was
run at 173 K in [D8]THF. A broad 1:1:1:1 quartet (1J-
d=81.6 and 82.0 ppm (each one with a J
and, as a shoulder of the latter doublet, two more doublets
(1J(13C,13C) ca. 13 Hz) at d=82.2 and 82.5 ppm were also ob-
(13C,13C)=11 Hz)
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
A
served (see inset in Figure 8d).
structure again appeared (Figure 8a). It was flanked on both
sides by three other broad peaks at d=81.8, 83.2 and
83.8 ppm and at d=73.0, 73.6 and 74.7 ppm, all correspond-
ing to quaternary carbon atoms. The CH2 region (57.0–
Moreover, the broad peak at d=74.7 ppm (Figure 8a)
now exhibits a fine structure with at least four 13C,13C cou-
ACTHNUTRGNEUNG
plings (1J(13C,13C)=12 Hz) (see inset in Figure 8d), and the
line widths of the peaks at d=73.0, 73.6, 83.2 and 83.8 re-
duced as a possible consequence of a missing 13C,7Li cou-
pling after 7Li decoupling. Homonuclear shift correlations
within a 13C,13C COSY spectrum (see Figure S12 in the Sup-
porting Information) together with concentration-dependent
ACTHNUTRGNEUNG
61.0 ppm) consisted of a doublet (1J(13C,13C)=11 Hz) at d=
58.6 ppm with a shoulder on the right side, two overlapping
broad doublets at d=58.8 and 58.9 ppm (1J(13C,13C) ca.
11 Hz), the latter with a shoulder on the left side (d=
AHCTUNGTRENNUNG
Figure 8. a), b) and c) refer to 13C{1H} NMR spectra of 0.2m lithiated [a,b-13C2]styrene oxide in [D8]THF at 173 K without TMEDA and after addition of
7
1.5 and 3 equivalents, respectively. d), e) and f) refer to 13C
{1 H, Li} NMR spectra of 0.2m lithiated [a,b-13C2]styrene oxide in [D8]THF at 173 K without
TMEDA and after addition of 1.5 and 3 equivalents, respectively. g), h) and i) refer to 7Li NMR spectra of 0.2m lithiated [a,b-13C2]styrene oxide in
[D8]THF at 173 K without TMEDA and after addition of 1.5 and 3 equivalents, respectively. Similar symbols in Figure 8d refer to quaternary and CH2
carbon atoms within
a
certain aggregate, as described in the legend. An asterisk in g)–i) indicates alkoxides/mixed aggregates with sBuLi.
!
&
*
Legend: monomer; ꢄ, , # stereoisomeric dimers; & bridged dimer; tetramer; * alkoxides/mixed aggregates with sBuLi.
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Carbenoid Chemistry
FULL PAPER
studies and warming experiments, that favoured the anion
decomposition (vide infra), allowed us to match all the qua-
ternary carbon atoms with the corresponding CH2 groups as
shown in Figure 8d.[49] The above results were always repro-
ducible. Upon addition of TMEDA (up to 3 equiv), a slight
downfield shift of the signal representative of the carbanion-
ic carbon at d=81.2 ppm took place (Dd=0.3 and 0.6 ppm
with 1 and 3 equiv of TMEDA, respectively), particularly
Hydrolytic kinetic resolution and deprotonation: DFT calcu-
lations suggested that in a fully-equilibrated solution of lithi-
ated styrene oxide in THF, a monomeric species such as [2a-
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
close in energy. As NMR spectra may be actually more
complicated than expected, owing to the possible presence
in solution of multiple stereoisomers for each aggregate be-
cause of epoxide chirality, we decided to synthesise a doubly
13C-enriched styrene oxide (enantiomerically enriched) in
order to investigate this aspect. The hydrolytic kinetic reso-
ACTHNUTRGNEUNG
noticeable in the corresponding 13C{1H,7Li} spectra (Fig-
ure 8e,f). The formation of a different type of ion pair dif-
fering in the degree of (lithium) solvation seems implausible
as the coupling with lithium was always preserved (Figur-
e 8b,c). A solvent-separated ion pair (SSIP), for example,
lution of [a,b-13C2]styrene oxide catalysed by [CoIII
ACHTUNGTRENNUNG(S,S)-
(salen)]OAc complex[53] furnished the chiral nonracemic (S)-
[a,b-13C2]styrene oxide 1 (25%, e.r. 99:1; see Experimental
Section; Scheme 3).
1
would give rise to a rather drastic change in both the H and
13C NMR spectra of the anion 2.[50] In the 1H NMR spec-
trum, two main sets of aromatic protons (at d=6.58 and
6.91 ppm, of the same kind of those depicted in Figure 5d,e)
continued to be present without any change in their chemi-
cal shifts. We therefore assigned the carbanionic carbon
peak moving at higher d values to the TMEDA-solvated
À
monomer, in which just a slight lengthening of the C Li
Scheme 3. Hydrolytic kinetic resolution of [a,b-13C2]styrene oxide 1.
bond may take place. Similarly, in the case of aryllithium re-
agents, monomeric TMEDA complexes have shown a very
high lability to ligand exchange.[51] It has been reported that
the relative affinities of TMEDA and THF for lithium may
be highly substrate-dependent.[52] On the basis of the above
results, we conclude that TMEDA competes with bulk THF
for coordination sites on lithium at least relatively to the h1-
monomeric aggregate. As far as the signals in the range
81.0–83.0 ppm are concerned, they tended to merge in a
major one as the amount of TMEDA increased (Figure 8b,c
and 8e,f), whereas those falling at d=73.0 and 74.7 ppm
were not influenced at all by added TMEDA. This co-sol-
vent, however, favoured the peak at d=73.6 ppm to be coa-
lesced with that at d=73.0 ppm, the intensity of which also
A 0.15m sample of the above optically active epoxide in
[D8]THF was treated with 1.2 equivalents of sBuLi in the
ACTHNUTRGNEUNG
absence of TMEDA and a 13C{1H,7Li} NMR spectrum was
run at 173 K. Because lithiated styrene oxide is known to be
configurationally stable, having employed a chiral nonrace-
mic substrate, only homochiral aggregates are expected to
form. Compared to the 13C NMR spectrum shown in Fig-
ure 8d, which refers to the deprotonation of a racemic sub-
strate, it is now worth noting the disappearance of only the
broad peak at d=83.2 ppm over the range 80.0–85.0 ppm
(Figure 9a).
In addition, over the range 72.0–76.0 ppm there was, ap-
parently, just a spectral simplification in between the two
main broad peaks at d=73.0 and 74.7 ppm (Figure 9a). The
7Li NMR spectrum (Figure 9c) consisted of sets of signals
7
increased (Figure 8b,c and 8e,f). Li NMR spectra revealed
that the signal at d=0.79 ppm (Figure 8g) was, as a matter
of fact,
a
broad doublet centred at d=0.71 ppm (1J-
7
U
similar to those depicted in Figure 8g. The acquisition of Li
the range 0.6–1.0 ppm as more TMEDA was added, similar
to the signal of the carbanionic carbon of the monomeric ag-
gregate (Figure 8h,i); therefore, they are related. Moreover,
in 7Li NMR spectra, addition up to three equivalents of
TMEDA also promoted a dynamic exchange and partial co-
alescence of the very broad signals in the range À0.5–
0.4 ppm (peaks at d=À0.48, À0.11, 0.20, 0.32 ppm, Figure 8
h,i) similar to that observed in the 13C NMR spectra (range
81.0–83.0 ppm, Figure 8e,f). Finally, as sBuLi reacted, three
more overlapping peaks at d=1.24, 1.32 and 1.38 ppm were
noted in 7Li NMR spectra (Figure 8h,i) reminiscent of a
spectra under simultaneous 13C decoupling proved to be cru-
cial in confirming the presence of a doublet at d=0.71 ppm
(Figure 9d) and a triplet at d=1.32 ppm; indeed, the latter
collapsed to give a singlet. However, this was visible only
after diluting the sample (0.075m) owing to the tail of sBuLi
(vide infra; compare also Figure 8i with Figure 9 f).
7Li,13C shift correlation: To assign and correlate the various
7Li resonances to the 13C nuclei of the several equilibrating
7
aggregates present in solution, a Li,13C heteronuclear multi-
ple quantum correlation (HMQC) experiment was set up
6
broad 1:2:1 triplet (1J
G
(Figure 10). In contrast with Li,13C shift correlation, which
suggestive of a lithium bonded to two 13C chemically equiva-
lent nuclei and the chemical shift of which did not change
during TMEDA titration (vide infra). Now, the question is
what about the nature of these several aggregates coexisting
in solution in slow equilibrium with the monomer?
is a well-established NMR technique,[54] to the best of our
knowledge this type of experiment has never been described
before.[55]
When a delay D2 =1= J of 16.7 ms for the preparation of
2
anti-phase magnetisation was used, the connectivity between
7
the Li,13C spin pairs showed a correlation between the 13C
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7967

V. Capriati, S. Florio et al.
Figure 11. 7Li,13C{1H} HMQC spectrum of 0.15m lithiated (S)-
[a,b-13C2]styrene oxide in [D8]THF at 173 K, pulse sequence of Figure 10,
D2 =16.7 ms, experimental time 19.22 min.
Figure 9. a) 13C
[a,b-13C2]styrene oxide in [D8]THF at 173 K. b) 13C
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
trum of 0.075m lithiated (S)-[a,b-13C2]styrene oxide in [D8]THF at 173 K.
c) and d) refer to 7Li NMR spectra of 0.15m lithiated (S)-
[a,b-13C2]styrene oxide in [D8]THF at 173 K acquired without and under
13C decoupling, respectively. e) and f) refer to 7Li NMR spectra of
0.075m lithiated (S)-[a,b-13C2]styrene oxide in [D8]THF at 173 K acquired
without and under 13C decoupling, respectively. An asterisk in c)–f) indi-
cates alkoxides/mixed aggregates with sBuLi. 4e and 7 refer to tetrameric
and four-centre dimeric structures, respectively (see Scheme 4 and the
body text).
sible explanation is that a four-centre homochiral dimeric
structure with coordination only to carbon (4e; Scheme 4)
may also be present in equilibrium in the reaction mixture.
Another correlation was established between the multiplet
7
at d=74.7 ppm (13C spectrum) and the broad Li signal at
d=0.60 ppm (Figure 11).
Scheme 4. A four-centre dimeric structure (4e) in equilibrium with a tet-
rameric aggregate (7).
Interestingly, this last connectivity was the only one seen
7
in the Li,13C HMQC spectrum when a delay D2 =50 ms, op-
1
timised for a J
N
7
Figure 10. Pulse sequence of Li,13C{1H} HMQC spectrum without 13C de-
coupling during acquisition.
the Supporting Information). This smaller J value at which
the above peak showed its highest intensity is suggestive of
the presence in solution of a higher aggregate, such as a
fluxional tetramer (7; Scheme 4; vide infra).[35] Not unex-
pectedly, the broadest lithium signals seen midway through
À0.50 to 0.40 ppm (Figure 9c) did not show any 13C correla-
tion, most probably because the transverse magnetisation
generated at the beginning of the pulse sequence (associated
to a fast transverse relaxation) was completely lost during
the delays involved in the experiment.[56]
Therefore, lithium peaks falling in the above range (À0.50
to 0.40 ppm) (Figure 9c) were tentatively assigned to the
carbon atoms present over the range 81.5–84.0 ppm as, simi-
larly to these carbon signals, the former experienced dynam-
ic effects in the presence of TMEDA. Lithium peaks at d=
signal at d=81.2 ppm with a lithium doublet ((13C,7Li)=
34 Hz) at d=0.72 ppm; a multiplicity that is consistent with
a lithium bound to only one carbon atom (Figure 11).
In addition, this type of experiment disclosed another in-
teresting correlation between the multiplet at d=73.0 ppm
in the 13C spectrum (usually unresolved) and a broad lithium
triplet (reminiscent of 1:2:1 intensities) (J
A
at d=1.32 ppm, which is consistent with a lithium bound to
two chemically equivalent 13C carbon atoms. In the Li spec-
7
trum this broad triplet is usually covered by the tail of
sBuLi when an excess of base is used (Figure 8 g-i). A plau-
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Carbenoid Chemistry
FULL PAPER
0.50 and 0.57 ppm (Figure 9c) were associated to alkoxides/
mixed aggregates (see Figure 5 f).[57]
Concentration-dependent studies: The above NMR sample
(0.15m) was then diluted with [D8]THF (0.5 mL) in order to
obtain a 0.075m solution and run again at 173 K. Dilution,
in principle, should break down higher aggregates into
smaller ones. Indeed, relative amount of the various species
present in the reaction mixture exhibited a dependence on
the total concentration in oxiranyllithium (Figure 9b). In
particular, over the range 81.0–84.0 ppm, the two doublets
at d=81.6 and 82.0 ppm underwent a strong decrease in
their intensity with respect to the peak at d=81.2 ppm, as-
signed to the THF-solvated monomer (Figure 9b). Two
pairs of doublets are now clearly visible (see inset in Fig-
ure 9b); the intensities of the more downfield-shifted ones
(peaks at d=82.5, 82.2 ppm) together with that of the broad
peak at d=83.7 ppm do not change much. On the other
hand, the relative concentrations of species 4e and 7 (Fig-
ure 9a,b and Scheme 4) changed after dilution, as was ob-
served in the change of intensity for the signals in the range
72.5–75.0 ppm, that of 4e rising apparently at the expense of
that for 7, the intensity of which decreased instead. This
means that 7 should be more aggregate than 4e. These last
two species, namely 4e and 7, could in principle be quanti-
tated at 173 K as their signals are well resolved. However, a
Scheme 5. Proposed mechanism for the interconversion of diastereoiso-
mer [4bACTHNUGTERN(UNGN thf)2] into [4b’ACHTUGTNRENNUG(thf)2] through [4bACHTUNGERTG(NNUN thf)ACHTNUGERTN(NUGN tmeda)].
and being also under slow equilibration on the NMR time-
scale (Scheme 5).[61]
On the basis of the above assumption, we tentatively as-
signed the broad signal at d=83.8 ppm to the other homo-
chiral bridged dimer, that is [4cACHTNUGTRENUNG(thf)2]; it could be similarly
affected by such a dynamics because of the broadness of its
linewidth. On the other hand, the signal disappearing at d=
83.2 ppm after employing chiral nonracemic styrene oxide
may correspond to a possible heterochiral dimer such as
plot of log[7] vs logACHTUNGTRENNUNG
[4e] showed a slope of 1.40.[58] An equi-
librium between a dimer and a trimer seems unlikely as
cyclic trimers of organolithium compounds are very rare
and, to our knowledge, have never been observed in polar
solvents such as THF.[59] Taking also into account indications
arising from 13C,7Li shift correlations, we interpret the above
deviation in terms of a slow equilibration on the NMR time-
scale between a fluxional tetramer and a four-centre dimer,
both being homochiral (Scheme 4).[60] Then, we tried to in-
terpret signals that relate to quaternary lithiated carbon
atoms between 80.0–85.0 ppm in 13C NMR spectrum which
did not give any 7Li correlation in 2D HMQC spectrum.
[4a
favour the interconversion between diastereomers [4b
and [4b’(thf)2], may occur after a decoordination of one of
the two oxirane oxygen atoms or, alternatively, THF desol-
vation. This interpretation would also give a rationale to the
coalescence observed in the presence of TMEDA over the
range 80.0–85.0 ppm (Figure 8b,c,e,f). TMEDA, in fact, may
ACHUTGTNNERNUG(thf)2] or [4dACHTNUGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
promote for a dimer such as [4b
tween the two diastereomeric aggregates [4b
(thf)2] through [4b(thf)(tmeda)] just competing with THF
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
for coordination sites on lithium (Scheme 5). Unfortunately,
we were not able to calculate the lithium inversion barrier
because of the anion decomposition at a higher temperature
than 173 K (vide infra).
Lithium as a centre of chirality: Among the four THF-sol-
vated dimers ([4a
ACHTUNGTRENNUNG(thf)2]–[4dACHTNUGTRENNUNG
tions to be in equilibrium with the monomer [2aACHTUNGTRENNUNG
two candidate homochiral dimers to be taken into consider-
ation when using a doubly 13C-enriched and optically active
À
À
C O and C Li bonds in a-lithiated ethers: a-Lithiated
À
ethers are known to be carbenoid species with elongated C
styrene oxide would be [4b
G
N
O bond lengths between the anionic carbon and the oxygen
À
ed dimer [4b(thf)2], in particular, has been shown to change
G
atoms relative to the C O bond lengths in the correspond-
ing non-lithiated species. The higher the electrophilic char-
À
its structural features, owing to partial breaking of some Ca
Li bonds. In this situation, there would be a partial destruc-
tion of the molecular symmetry as one of the two lithium
atoms becomes a centre of chirality. Therefore, two diaste-
À
acter, the more elongated the carbenoid C O bonds and the
larger the downfield shift of the carbenoid 13C atom.[7b–d,11]
However, that a dimeric organolithium compound, deriving
from organic ring systems containing a heteroatom (e.g., N,
O, S), may exhibit a solution structure different from that of
“classic” bridged dimers (in which two bridging organic
group participate in three-centre two-electron bonds) has
precedent in the literature.[62] In view of this, the fine struc-
ture exhibited by the peak at d=74.7 ppm (assigned to a ho-
mochiral tetrameric aggregate), and observed only after run-
reomers ([4bACHTUNGTRENNUNG(thf)2] and [4b’ACHTUNTGERN(NGUN thf)2]; Scheme 5) are expected
to form, each one exhibiting a pair of diastereotopic lithiat-
ed carbon atoms. In this view, one possible interpretation of
the two pairs of doublets seen midway 80.0–85.0 ppm may
be that they would be just related to two pairs of diastereo-
topic lithiated carbon atoms within two diastereomeric di-
À
meric aggregates both having partially closed C Li bonds
Chem. Eur. J. 2009, 15, 7958 – 7979
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7969

V. Capriati, S. Florio et al.
ning a 13C
tively interpreted in terms of four overlapping doublets
owing to 13C,13C couplings (1J
representative of a diastereotopic and therefore unisochro-
nous carbanion carbon atom making up part of a nonsym-
metric C4Li4 tetrameric core, most probably again owing to
G
ACTHNGUTERNNUG
doublets [because of 13C,13C coupling (J(13C,13C)=11 Hz)],
the value of the former coupling constant lying again within
the typical range of monomeric species. Unfortunately, the
signals of the other carbanionic carbon atoms, falling either
down- or upfield with respect to that of the monomeric ag-
gregate, continued to appear as broad singlets. Most likely,
possible different intradimer Ca-Li and/or Li O bond types
ACTHNGUTERNNUG
for a coupling constant value 1J(13C,6Li) lower than 12 Hz
À
present.[63, 64]
(as one would be expected for higher aggregates)[35] the co-
presence of a small (11 Hz) 13C,13C coupling constant allows
both couplings to merge into unresolved peaks.
In an attempt to shed more light on the “nature” and the
structure of the various aggregation states of lithiated sty-
rene oxide in solution, we ran other experiments this time
7
employing sBu6Li as the base. In fact, the faster Li quadru-
Effect of temperature: Effect of temperature on the thermal
stability of a-lithiated styrene oxide has also been investigat-
ed. A 0.2m sample of [a,b-13C2]oxiranyllithium (2), prepared
using one equivalent of sBu6Li and three equivalents of
TMEDA, was gently warmed from 173 to 232 K: four new
pole relaxation generally leads to line broadening and there-
by masking line splitting, whereas scalar spin–spin J cou-
plings to neighbouring nuclei could be better resolved in the
6
case of Li, because of the favourable properties of this iso-
À
tope (I=1, very small quadrupole moment).
pairs of doublets, each one corresponding to a C H carbon
(as confirmed by a DEPT-135 analysis), formed in the corre-
sponding 13C NMR spectrum (Figure 13c) in addition to
those discussed above (Figure 7a): two doublets centred at
13C, 1H, 7Li and 6Li NMR spectroscopic studies—
[a,b-13C2]styrene oxide: lithiation with sBu6Li
d=101.3 (1J
78 Hz), the other two at d=158.4 (1J
159.5 ppm (1J(13C,13C)=78 Hz). By quenching of the reac-
(13C,13C)=78 Hz) and 102.3 ppm (1J
ACHUTGTNRENNUG CAHTUNGTRENNUNG
13C NMR investigation in [D8]THF at 173 K: sBu6Li (96%
enrichment) was more conveniently prepared, with respect
to the reported experimental procedure which makes use of
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
tion mixture with CH3OH, one of the main byproducts de-
tected by H NMR spectroscopy and GC-MS analysis in the
6
1
6Li dispersion (5% Na) in pentane,[65] from Li and 2-chloro-
butane under sonic waves as in the case of nBu6Li (see Ex-
perimental Section).[66] A sample of [a,b-13C2]oxiranyllithium
(2) in [D8]THF (0.3m, prepared by treatment 1 equiv of sty-
rene oxide with 1.2 equiv of sBu6Li) was run at 173 K with-
out TMEDA. The resulting 13C NMR spectrum (Figure 12)
was very similar to the one obtained by using sBu7Li in ab-
ACTHNUTRGNEUNG
sence of TMEDA (0.2m), but run as 13C{1H,7Li} (Figure 8d).
The “apparent quartet” centred at d=81.2 ppm may be in-
terpreted as the result of the split of a triplet [because of
ACHTUNGTRENNUNG
13C,6Li coupling (J(13C,6Li)=12 Hz)] into three overlapping
Figure 13. 13C NMR spectra of 0.2m lithiated [a,b-13C2]styrene oxide ob-
tained using 1 equivalent of sBu6Li and 3 equivalents of TMEDA at
173 K (trace a), 199 K (trace b), and 232 K (trace c). s stands for starting
Figure 12. 13C NMR spectrum of 0.3m lithiated [a,b-13C2]styrene oxide in
[D8]THF at 173 K obtained using sBu6Li in absence of TMEDA.
styrene oxide. Legend: monomer; # stereoisomeric dimers; & bridged
&
!
!
,
*
dimer; tetramer;
, * CH vinylic carbon atoms.
7970
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Chem. Eur. J. 2009, 15, 7958 – 7979

Carbenoid Chemistry
FULL PAPER
crude mixture was phenylacetaldehyde (9; Scheme 6). On
the basis of these results and considering the large upfield
shift associated to two pairs of signals (d=101.3 and
102.3 ppm), we assigned the above peaks to the vinylic
Scheme 6. 1,2-H Shift rearrangement of a-lithiated styrene oxide 2 leads
to phenylacetaldehyde 9 through enolates 8.
Figure 14. Partial 13C NMR spectrum of 0.2m lithiated [a,b-13C2]styrene
oxide in [D8]THF at 173 K obtained using 1 equivalent of sBu6Li and
3 equivalents of TMEDA. Regions displayed show, in particular, signals
relating to a-(a’-) and b-(b’-)-carbon atoms representative of different ag-
gregates of b-lithiated [a,b-13C2]styrene oxide.
carbon atoms of lithium enolates of phenylacetaldehyde 8
being detected as a mixture of two diastereoisomers (Fig-
ure 13c). In fact, such a large high-field shift detected for an
sp2 carbon atom could be explained just in terms of an in-
crease in the p-electron density, as in the case of a “carbonyl
carbon atom” of a metal enolate. In the case of the lithium
enolate of acetophenone, the two vinylic carbon atoms have
been reported to fall in THF at d=97.1 and 162.5 ppm.[67] It
is reasonable that such a mixture of diastereomeric enolates
may stem from a rearrangement of the oxiranyllithium
through a 1,2-H shift (Scheme 6).[1f]
Therefore, this type of rearrangement seems to be the
preferred ring-opening pathway of a-lithiated styrene oxide
after warming the reaction mixture in the absence of orga-
nolithium. What also emerges from an analysis of events de-
picted in Figure 13 is that aggregates with signals between
80.0–84.0 ppm (monomer and stereoisomeric dimers) are
the most prone to undergo a ring-opening process, followed
by that with a signal at d=73.0 ppm (bridged dimer), where-
as the aggregate with a signal observed at d=74.7 ppm
(tetramer) resulted to be the least “reactive”, as one would
be expected.[52] This type of investigation also allowed us to
match the carbanionic carbon
carbon atoms with signals at d=90.8 and 92.6 ppm (which
appeared as broad poorly resolved signals, again in a rela-
tive ratio of ca. 3:1) because, as the temperature is in-
creased, the intensities of all the aforementioned peaks
tended simultaneously to go down until disappearing. One
possible interpretation of the above results is that styrene
oxide might also undergo a b-lithiation to some extent (less
than 5%) to give 10 (Figure 14). If this is true, this “unstabi-
lised” oxiranyllithium should have a stronger carbenoid
character than 2 considering the highest d values exhibited
by the carbanionic carbon atoms (b and b’, Figure 14), rep-
resentative of aggregation states still undefined.
The presence of such a lithiated isomer would also pro-
vide a rationale to the formation in the reaction mixture of
trans-3-methyl-1-phenyl-pent-1-ene (5; Figure 7, Scheme 7)
as a consequence of a competitive attack of sBuLi just on
atoms with signals at d=73.0,
74.7 and 82.5 ppm to the CH2
carbon atoms with signals at
d=60.3, 59.2 and 59.1 ppm, re-
spectively.
b-Lithiated styrene oxide: By
rigorous
13C NMR spectrum obtained
from deprotonating
inspection,
the
Scheme 7. Competition between a- and b-lithiation of styrene oxide leads to compounds 11 and 12 by means
[a,b-13C2]styrene oxide with one
equivalent of sBu6Li in the
presence of three equivalents of
TMEDA at 173 K (0.2m, Fig-
ure 13a) revealed the presence
À
of an in situ quenching with Me3SiCl. The interference of an intermolecular C Li insertion reaction leads to
alkene 5 through a stereospecific Li2O elimination.
of two more pairs of small doublets (because of 13C,13C cou-
plings, 1J(13C,13C)=15 Hz) at d=61.0, 61.3, 61.9 and
the b-lithiated position of styrene oxide. This result also im-
plies that the initially formed b-lithiooxirane 10 retains its
configurational integrity on the timescale of the reaction
and that the final elimination step of Li2O is stereospecific.
Indeed, it has been reported[1h,68] that in the case of terminal
alkyl-substituted epoxides, the metalation occurs at the pri-
ACHTUNGTRENNUNG
62.2 ppm; the pair shifted to high-field being almost three
times more intense with respect to the others, all corre-
À
sponding to C H carbon atoms (DEPT-135-analysis;
À
Figure 14). They were tentatively assigned to the two C H
Chem. Eur. J. 2009, 15, 7958 – 7979
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7971

V. Capriati, S. Florio et al.
Table 1. Comparison of the theoretical and experimental 13C NMR shieldings [ppm][a] in free (2a) and solvated lithium salt.
B3LYP/6-311+G
B3LYP/6-311+G
2a
N
B3LYP/6-311+G
B3LYP/6-31+G(d)
[2a(thf)2]
E
B3LYP/6-311+G
B3LYP/6-31+G(d)
[2a(thf)2] ACHTUNGTRENNUNG[2aACHTUNGTRENNUNG(thf)3]
ACHTUNGTRENN(UNG 2d,p)//
Position
Exptl[b]
2a
N
R
G
2a
G
U
a
81.2
58.6
109.3
72.2
108.9
72.2
97.7
68.0
80.7
59.3
108.6
71.7
97.0
67.8
80.3
58.9
b
ipso
ortho
meta
para
MUE[c]
SDU[d]
162.5
122.2
127.5
119.7
162.8
126.0
133.2
127.8
9.93
162.6
127.0
134.1
128.1
10.20
9.65
168.4
127.7
133.6
125.6
8.17
4.16
173.7
127.3
133.8
122.9
4.50
4.02
0.60
162.1
126.2
133.2
127.2
9.68
9.64
167.3
126.9
132.6
124.5
7.40
4.47
173.0
126.4
132.7
121.8
3.87
3.76
0.60
9.95
20.85
MUE
(Ca+Cb)
20.65
12.95
20.25
12.50
[a] Relative to TMS. [b] These values refer to the [D8]THF-solvated monomeric species, in absence of TMEDA, at 173 K. [c] Mean unsigned (absolute)
error. [d] Standard deviation on unsigned values.
mary carbon atom, generally from the less hindered site
with a high E selectivity particularly when using secondary
and tertiary alkyllithium species.
and results are summarised in Table S5 in the Supporting In-
formation and in Table 1. As it can be noted, chemical shifts
were nicely reproduced by the calculations for the b- and
the a-carbon atom of monomeric oxiranyllithium only when
To support the hypothesis that a stereospecific anti-b-de-
protonation really competes with a-deprotonation, a solu-
tion of styrene oxide in THF (0.5m) containing 1.2 equiva-
lents of (CH3)3SiCl was treated with 1.2 equivalents of
sBuLi at 173 K (in situ quenching conditions). Besides the
expected a-trimethylsilylstyrene oxide (11) from 2 (93%),
5% of trans-b-trimethylsilylstyrene oxide (12)[69] from 10
was also isolated together with 2% of alkene 5 (Scheme 7).
Provided that an anti-metalation reaction occurs, the stereo-
specific formation of the trans-alkene 5 may be consistent
either with an anti-substitution reaction followed by a syn-
Li2O elimination or with a syn-substitution reaction fol-
lowed by an anti-Li2O elimination (Scheme 7). As the coor-
dination between lithium and oxygen is highly favourable
because of the high lattice enthalpy of Li2O
(2799 kJmolÀ1),[70] a syn-elimination of Li2O seems to be the
most likely to occur.
a third molecule of THF is introduced (MUEACHTUNGTRENNUNG(Ca+Cb)
0.60 ppm) (Table 1). An even larger downfield shift was pre-
dicted for the a-lithiated carbon atom in the case of free
nonsolvated species, which, therefore, should have a stron-
ger carbenoid character. But, what about the dimers?
Again, a good agreement between the experimentally ob-
served values (MUE 1.40 ppm) and the calculated chemical
shieldings could be found for the main homochiral diaste-
reomeric aggregate, namely [4cACHTNUGTRENUNG(thf)2], shifted downfield
with respect to the monomer (entry 3, Table 2).[72] The calcu-
lations predict a more downfield shift and thus more carbe-
noid character at the a-carbon for all the solvated dimers
([4aACHTNURTGENN(UG thf)2]–[4dAHCTUNGTRNEN(UGN thf)2]; Table S6, Supporting Information).
The observation of a more upfield shift for the Ca atom
upon solvation as found for the monomer was reproduced
for the homochiral dimers ([4b
ever, a more downfield shift was observed for the heterochi-
ral isomers [4a(thf)2] and [4d(thf)2] (Table S6, Supporting
ACHUTGTNERN(GUN thf)2] and [4cACHTUNGTRENN(UGN thf)2]). How-
Gauge independent atomic orbital (GIAO) calculations:
The intriguing downfield 13C
A
ACHTUNGTRENNUNG
shifts observed for the carba-
Table 2. Comparison of experimental and theoretical Ca and Cb 13C NMR shieldings [ppm][a] in solvated
dimers (4) of lithiated styrene oxide.
nionic carbon atoms of the mo-
nomer and the mixture of ste-
reoisomeric dimers with partial-
Position
Exptl
[4a
E
[4b
E
[4c
G
[4d
G
ACHTUNGTRENNUNG[4eACHTUNGTRENNUNG(thf)2]
1
2
3
4
5
a
82.35[b]
58.85[b]
94.0
61.4
7.10
94.0
61.4
7.38
94.0
61.4
5.40
94.0
61.4
11.05
94.0
61.4
7.05
87.9
65.5
6.10
87.9
65.5
6.38
87.9
65.5
3.80
87.9
65.5
10.05
87.9
65.5
6.05
86.5
62.1
3.70
86.5
62.1
3.98
86.5
62.1
1.40
86.5
62.1
7.65
93.8
61.7
7.15
93.8
61.7
7.43
93.8
61.7
5.15
93.8
61.7
11.10
93.8
61.7
7.10
69.4
55.4
8.20
69.4
55.4
7.93
69.4
55.4
10.50
69.4
55.4
4.25
69.4
55.4
8.25
À
ly Ca Li broken bonds, as well
b
as the upfield 13C shift presum-
ably related to a four-centre
dimer, raise the question
whether they accord or not
with a theoretical model. To
check this, NMR shielding ten-
sors were predicted with the
gauge independent atomic orbi-
tal (GIAO) method[71] (see
MUE
a
81.8c
b
58.85[c]
MUE
a
83.8
62.0
b
MUE
a
73.0
60.3
b
MUE
a
83.2
58.1
86.5
62.1
3.65
Computational
Methods).
b
Structures and NMR shielding
values for neutral and both the
free and solvated lithium salt of
MUE
[a] Calculated using B3LYP/6-311+G
the shifts for the downfield shifted diasteromer of [4b
(thf)2].
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
styrene oxide were calculated shifted diasteromer [4b
ACHTUNGTRENNUNG
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Chem. Eur. J. 2009, 15, 7958 – 7979

Carbenoid Chemistry
FULL PAPER
Information). For the b-carbon, the signals for both the mo-
nomer and the dimers experience a more upfield shift upon
solvation (Table 1 and Table S6, Supporting Information).
observed for the monomer and the value indicates that [4c-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
Interestingly, none of the dimers ([4aACHTNUGRTENNUG(thf)2]–[4dACHTUTGNREN(NUGN thf)2])
fitted with the upfield shift of the signal at 73.0 ppm found
for Ca in one of the co-existing aggregates. Therefore, a so-
lution to this was sought by introducing additional structures
(Figure S14, Supporting Information). The only structure
that fitted with such an upfield shift (MUE 4.25 ppm) was
found when lithium was constrained to coordinate only to
ACHTUNGTRENNUNG
stronger carbenoid character than [2aACTHUNGTRENNUNG
with available experimental data.
Factors affecting the carbanionic/carbenoid reactivity of
lithiated styrene oxide: Factors responsible of a nucleophil-
ic/electrophilic behaviour of lithiated styrene oxide at 173 K
in a polar solvent such as THF (which are our standard con-
ditions) were also experimentally investigated. We set up
the following experiments on the laboratory scale: two solu-
tions of styrene oxide 1 in THF with different concentra-
tions (0.05 and 0.5m) were treated separately, at 173 K, each
one with 1.2 equivalents of sBuLi preliminarily in absence
of TMEDA and the resulting mixtures quenched one hour
after with CH3OD. In both cases, the amount of alkene 5,
formed from a “reductive alkylation” process, was very low
(3-5%), with the percentage of a-deuteration of [D1]-1 rang-
ing from 82 to 93 (0.05 and 0.5m, respectively; Table 3).
the Ca atoms ([4eACHTUNGTRENNUNG(thf)2]), thus without oxirane oxygen coor-
dination (Scheme 4 and entry 4, Table 2). We therefore
assign the signals at 73.0 and 60.3 ppm to the Ca and Cb
atoms, respectively, of such a structure, possibly with addi-
tional solvent molecules coordinated. The assignment of the
broad peak at 83.2 ppm originating from heterochiral iso-
mers was found less accurate (entry 5, Table 2), and might
therefore involve complexes with different solvent shell
than modelled. A slight shift was also observed for the four
peaks between 81.2–82.5 ppm assigned to the two equilibrat-
ing diastereoisomers of [4bACTHNUTRGNE(UNG thf)2] (entries 1 and 2, Table 2);
this might be due to the dynamic effect experienced by
these isomers.
Table 3. Competitive formation of byproducts 5 and 13 in deprotonation/
deuteration of styrene oxide 1 in THF at 173 K according to the presence
or absence of TMEDA and to the molar concentration.
Natural bond orbital (NBO) analysis: In addition to the
NMR analysis on the carbenoid character exhibited by both
monomer 2a and dimers 4 and their solvated analogues pre-
sented above, we have analysed the energies of the s and s*
orbitals in the oxirane ring. As described in previous studies
by Boche and co-workers in the case of carbenoid species,[7c]
a lowering of the energy of the s*OÀCa orbital and simultane-
ously an elevation of the energy of the sOÀCa orbital is ex-
pected for styrene oxide when it is lithiated, resulting in a
decreased energy gap (DE) between the two orbitals. A
comparison of the orbital energies calculated using NBO
analysis, as seen in Table S7 (Supporting Information),
shows that on going from the neutral styrene oxide to the
lithiated unsolvated monomer 2a, DE is lowered from 0.93
to 0.66 au. The largest contribution to this is the elevation of
the sOÀCa orbital, while the lowering of the s*OÀCa orbital
contributes less. Tri-solvation of monomer 2a enlarges DE
mainly because of elevation of the s*OÀCa orbital, which in
fact now has an energy that is higher than the corresponding
orbital energy in the neutral compound. At a first glance,
looking at only the energy of the s*OÀCa orbital, one could
molar
concentration
TMEDA
equiv
epoxide
alkene
diol
[D1]1 [%D][a,b]
5 [%][b]
13 [%][b]
0.05
0.5
0.05
0.5
0.05
0.5
–
–
1
1
3
3
82
93
84
73
96
95
3
5
4
2
3
2
<1
15
2
4
2
4
[a] Deuterium incorporation was established by 1H NMR analysis.
1
[b] Relative ratios were established by H NMR analysis on the crude re-
action mixture.
However, in the case of 0.5m solution, in addition to the
above byproduct, a mixture of diastereomeric enediols 13
(d.r. ca. 2:1; as the result of an “eliminative dimerisation”
reaction between two units of lithiated styrene oxide) was
also isolated in 15% yield, whereas employing a 0.05m solu-
tion the formation of enediols 13 dropped back to less than
1% (Table 3). By adding TMEDA to a 0.05m solution of
styrene oxide 1 in THF, the only difference detected was
just the increase in the percentage of a-deuteration of [D1]-
1 from 84 (1 equiv TMEDA) to 96% (3 equiv of TMEDA),
the percentage of alkene 5 and enediols 13 being always
rather low, 3–4 (1–3 equiv TMEDA) and 2% (1–3 equiv
TMEDA), respectively. On the other hand, in the case of
interpret the data as the lithiated compound [2aACHTNUTRGNEUNG(thf)3]
having less carbenoid character than the neutral compound.
However, since we know from both the NMR experiments
and GIAO calculations that the chemical shift for the a-
carbon is shifted downfield upon lithiation, the interpreta-
tion needs to be based on the DE value.
Dimerisation of 2a leading to a dimer such as 4c results
in a DE of 0.71, thus in between 2a and [2aACTHNURTGNENG(U thf)3] of which,
again, the major contribution to the energy change is from
the elevation of the sOÀCa orbital. Subsequent solvation
gives [4c
ACHTUNGTRENNUNG(thf)2], which has a computed DE of 0.73. Here, the
solvation has a smaller effect on the s*OÀCa orbital than that
Chem. Eur. J. 2009, 15, 7958 – 7979
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V. Capriati, S. Florio et al.
0.5m solution, the percentage of deuteration increased from
73 (1 equiv TMEDA) up to 95% (3 equiv TMEDA), where-
as that of alkene 5 and enediols 13 remained around 2 (1–
3 equiv TMEDA) and 4% (1–3 equiv TMEDA), respective-
ly. In summary, dilution, favouring the monomeric species,
which has a lower carbenoid character with respect to ste-
reoisomeric dimers (4a–4d), is surely a crucial factor in fa-
vouring a nucleophilic/basic behaviour for lithiated styrene
oxide at a temperature as low as 173 K also in absence of
TMEDA. At a higher concentration, lithiated styrene oxide
is more prone to self-associate to give higher aggregates
or lower temperature than 173 K, presence or absence of
TMEDA. DFT calculations by using B3LYP suggested that
in THF, lithiated styrene oxide may be present as a di-sol-
vated bridged dimer or as a tri-solvated monomer. The
latter, with no coordination between Li and the oxirane ring
oxygen and with an almost tetrahedral arrangement around
the carbanionic carbon, is the most stable species with a
negligible delocalisation of the p charge into the phenyl ring
(not higher than 10%).
A multinuclear magnetic resonance investigation per-
formed on lithiated [a,b-13C2]styrene oxide (obtained depro-
tonating the parent epoxide with both sBu7Li and sBu6Li)
showed that a-lithiated styrene oxide (in agreement with
calculations) is mainly present in THF at 173 K, over a
range of concentration 0.075–0.3m, as a THF-solvated mon-
omeric species (2a) in equilibrium with dimers (4), the
NMR signals of which are shifted more downfield
(Scheme 8). However, NMR spectra resulted to be actually
more complicated than expected, because of the possibility
of multiple stereoisomers in solution, in particular for the di-
meric aggregates 4. A factor of further complication was
also the reduced symmetry of some aggregates mainly be-
À
such as dimers 4a–4d with partially Ca Li broken bonds,
which proved to have a more pronounced “carbene-like” re-
activity and are most probably responsible of the formation
of the diastereomeric enediols 13; this is because the higher
the concentration of solution, the higher the amount of
these type of dimers formed. This tendency may be cut
down by adding TMEDA to the reaction mixture.
Another factor able to tune the type of reactivity of lithi-
ated styrene oxide is the temperature: at a temperature
higher than 173 K, a-lithiated styrene oxide tends to be
easily attacked by excess sBuLi (if any) to give alkene 6
(“reductive elimination” reaction, see Figure 7) as well as to
À
cause of the partial breaking of some Ca Li bonds. These
undergo 1,2-H shift to give phenylacetaldehyde
9
findings were supported by GIAO chemical shift calcula-
tions, which are in good agreement with the experimental
values found for both the solvated monomer 2a and the
dimers 4. NMR studies performed on the optically active
lithiated (S)-[a,b-13C2]styrene oxide, together with concen-
tration-dependent studies, indicated that at least two homo-
(Scheme 6). Moreover, because b-deprotonation competes
to some extent, the presence of alkene 5 in the reaction mix-
ture cannot be avoided also at 173 K (Scheme 8).
Conclusions
chiral dimers (such as [4b
volved. One of these ([4b
G
ACHTUNGRTEN(NNUG thf)2]) should be in-
AHCTUNGTRENNUNG
In conclusion, the dichotomic reactivity exhibited by lithiat-
ed styrene oxide in THF has been related to the aggregation
states favoured in solution according to the employed exper-
imental conditions: diluted or concentrated solutions, higher
ture of two diastereomers in slow equilibration on the NMR
timescale, each having a pair of diastereotopic lithiated
carbon atoms because of the chirality at lithium (Scheme 5).
Increasing amount of TMEDA seems to promote a faster
Scheme 8. Proposed two-step mechanism for a- and b-lithiation of styrene oxide and for the formation of alkenes 5 and 6, enediols 13 and PhCH2CHO 9
through different aggregation states.
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Chem. Eur. J. 2009, 15, 7958 – 7979

Carbenoid Chemistry
FULL PAPER
exchange on the NMR timescale between the above epimers
at lithium. In addition to the aforementioned aggregates,
signals corresponding to two other types of aggregates
slowly equilibrating on the NMR timescale could be seen at
a higher field. A 13C,7Li HMQC shift correlation, in addition
to confirm the presence of the monomer 2a (doublet, 1J-
the presence of three equivalents of TMEDA would testify
its stronger electrophilic character with respect to 2a.
Indeed, once styrene oxide is lithiated with sBuLi, the for-
mation of trans-alkene 5, as a consequence of a reductive al-
kylation reaction promoted by the organolithium on the b-
lithiated regioisomer, cannot be avoided in any way.
A
In conclusion, lithiated styrene oxide would represent an-
other wonderful example on the “theme of polarities”[75] as
its carbanionic/carbenoid character would be just the poles
of another duality. The best explanation to justify the efforts
made by the authors of the present paper to unravel the “se-
crets” and decode the “language” of such a double-faced
lithiated system may be found in the words of Roald Hoff-
mann: “Tension gives life, the potential of change… Each
fact or process of the science, and the way these are viewed,
is in precarious balance between polar extremes. And the
polarities of substances and their transformations resonate
with forces deep in our psyche”.[75] Styrene oxide “progeny”,
we are sure, will have in store new interesting and exciting
surprises.
carbon-only chelated dimer (such as 4e; triplet, JACTHNUTRGNEUNG
(13C,Li) =
16 Hz) and a fluxional tetrameric aggregate (7), the cross-
1
peak of which was the only one seen in the 2D experiment
ACTHNUTRGNEUNG
once it was set up with an optimised 1J(13C,Li)=10 Hz
(Schemes 4 and 8). The intriguing high-field shift observed
for the signals of the bridged dimer 4e with respect to the
mixture of O-coordinated stereoisomeric dimers (4aACHTUNTRGNEUNG(4d),
4b, 4c, low-field shifted) was also supported by GIAO cal-
culations.[73]
The above 2D-HMQC experiment, which is described for
the first time in the present paper, is undoubtedly a new and
invaluable tool for structural studies of organolithium com-
pounds in solution and which complements other routine
NMR techniques. Dilution was also proven to be a crucial
factor in favouring the monomeric aggregate in solution
versus dimeric aggregates with signals that are shifted to
low-field, the latter being also the expression of a higher
“carbene-like” reactivity of lithiated styrene oxide. In sup-
port of this, NBO analysis indicated that a O-coordinated
Experimental Section
General: Glassware was dried overnight in a 1208C oven (syringes and
Teflon-containing parts were dried at 508C in a vacuum oven) before
been transferred into a glovebox (Mecaplex GB 80 equipped with a gas-
purification system that removes oxygen and moisture) under a nitrogen
atmosphere. The typical moisture content was less than 0.5 ppm. All han-
dling of the lithium compounds was carried out in the glovebox with gas-
tight syringes. 2-Chlorobutane, cyclohexane and N,N,N’N’-tetramethyle-
thylenediamine (TMEDA) were distilled under a nitrogen atmosphere
over CaH2. Tetrahydrofuran (THF) was freshly distilled from sodium
benzophenone ketyl under N2. [D8]THF was stored over molecular sieves
(4 ꢃ) in the glovebox. Styrene oxide was of commercial grade (97%,
Sigma–Aldrich). Commercial solution of sBuLi (1.3m in cyclohexane)
was handled with septum and syringe-based technique and titrated
against dry THF using N-pivaloyl-o-toluidine prior to use.[76]
bridged dimer such as [4c
noid character than monomer [2aAHCNUTGTRENNUNG
ACHTUNGTRENNUNG
such dimeric aggregates might also be directly responsible
of the formation of enediols 13 (which are eliminative di-
merisation products) as their relative amounts increase at a
higher solution concentration in parallel with the increase of
dimers concentration (Scheme 8). In order to rationalise all
the experimental results described in the present paper, a
reasonable hypothesis is that lithiation of styrene oxide
could be described, on the whole, as a two-step process in
which the formation of a reactive pre-lithiation anti complex
(with respect to the phenyl group) between the substrate
and a monomeric sBuLi anticipates a rate-determining
proton transfer (Scheme 8). Such complexes have also been
previously postulated by Crandall[5a] and Molander[74] for ra-
tionalizing the regio- and stereoselectivity of numerous a-
and b-deprotonation reactions. Starting from the above che-
lated structures, two competitive pathways may operate for
the lithiation of styrene oxide to occur: a- (path b) and b-
deprotonation (path a). Once the most acidic a proton has
been extracted within the anti complex, the corresponding
a-lithiated species 2a may undergo a reductive alkylation
reaction and/or a 1,2-H shift reaction to give alkene 6 or
phenylacetaldehyde 9 (through enolates 8), respectively, ac-
cording to whether the reaction mixture is warmed to room
temperature in the presence or absence of sBuLi
(Scheme 8). At the same time, b-lithiation competes to
some extent (5%). The highest downfield shifts observed
for the signals corresponding to aggregation states (not fur-
ther investigated) of b-lithiated styrene oxide 10 at 173 K in
Preparation of sBu6Li: A block of 6Li metal (0.25 g, 41.6 mmol, 96% 6Li
purchased from Aldrich) was cut into small pieces using a sharp knife.
6
The Li metal was transferred into a 50 mL two-neck flask equipped with
silicone/Teflon septa. After this, dry cyclohexane (10 mL) was added and
the flask was put in an ultrasonic bath at 208C (Sonorex Super 10P oper-
ated at maximum effect) for about 3 min. Then, the mixture of lithium
hydroxide and cyclohexane was removed with a syringe, under a positive
pressure of argon, and another aliquot of cyclohexane (10 mL) was
added followed by ultrasonic bath for another 3 min. This procedure was
repeated several times until the cyclohexane solution remained clear and
the previously black lithium pieces had metallic surfaces. Upon addition
of dry cyclohexane (15 mL), followed by slow addition of 2-chlorobutane
(2.09 mL, 20.0 mmol) over 5 min, the flask was again put in the ultrasonic
bath for another 3 h at about 78C. The reaction started immediately and
was monitored by the change of the colourless solution to deep purple.
After 12 h of magnetic stirring at 10–158C under argon, the resulting
purple suspension was centrifuged and the supernatant was transferred
into a glass apparatus equipped with high-vacuum Teflon valves. The sol-
vent was removed under vacuum (10À4 torr). The concentration was
about 10m determined by a titration by NMR spectroscopy by using dii-
sopropylamine (with less than 5% alkoxides). The sBu6Li was stored
under argon atmosphere in a glass apparatus at À308C.
NMR spectroscopy—general information: NMR experiments were per-
formed in Wilmad tubes (5 mm) fitted with a Wilmad/Omnifit Teflon
valve assembly (OFV) and a Teflon/Silicon septum. All NMR spectra
Chem. Eur. J. 2009, 15, 7958 – 7979
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7975

V. Capriati, S. Florio et al.
were acquired using nonspinning 5 mm samples with deuterium field-fre-
quency locking on a spectrometer equipped with a direct custom-built
5 mm 1H, 7Li, 13C triple-resonance probe-head including a z-gradient coil
at the following frequencies: 599.944 (1H), 150.856 (13C), and
233.161 MHz (7Li). 13C NMR spectra were referenced internally to the
Acknowledgements
This work was carried out under the framework of the National Project
“Stereoselezione in Sintesi Organica. Metodologie ed Applicazioni” and
financially supported by the University of Bari and by the Interuniversi-
ties Consortium C.I.N.M.P.I.S. The authors are indebted to Prof. Gideon
Fraenkel (Ohio State University) for his interest and helpful suggestions
and for supporting preliminary NMR investigations on lithiated styrene
oxide. Albert Chow is also acknowledged for performing preliminary
DFT calculations on lithiated styrene oxide. S.O.N.L. gratefully acknowl-
edges Prof. Per Ahlberg for financial support of a post-doctoral stipend.
À
C O carbon atom of [D8]THF (d=67.45). Exponential multiplication
(LB) of 2–6 Hz was applied to 13C spectra. 7Li spectra were referenced
externally to 0.3m LiCl in [D4]MeOH (d=0.0). The typical pulse widths
for 908 pulses (ms) and attenuation levels (dB, in brackets) were the fol-
7
7
lowing: 13C: 12.50 (3.50); Li: 15 (1.50); Li-dec: 100 (18). The probe tem-
perature was calibrated using a methanol thermometer. 2D 13C,13C-
COSY was performed as reported.[77] The multiplicities are denoted as
follows: s=singlet, d=doublet, m=multiplet, dm=doublet of multiplets.
Selected 7Li,13C{1H} HMQC parameters: sweep width F1 (13C) 240 ppm,
F2 (7Li) 10 ppm; 4 scans per increment in F2; 256 increments recorded;
final matrix after zero filling, 1024 (F2)ꢄ1024 (F1); evolution delay, D2, of
1J (13C,7Li) variable from 8.3 to 50 ms, as described in the main body of
this paper; relaxation delay 1 s; acquisition time 0.11 s; sine multiplica-
tion of p/2 in F2 and Gaussian multiplication of LB=0.30, GB=0.1 in F1
prior to transformation (magnitude mode); total exp. time 19.22 min.
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NMR spectroscopy: representative procedure for the preparation of 0.2m
sample of lithiated styrene oxide at 173 K: An appropriate amount of
sBuLi (77 mL, 0.1 mmol, 1.3m in cyclohexane), preliminary filtered over
celite, was concentrated under reduced pressure in an NMR tube (assem-
bled as described and previously evacuated and purged with argon) and
the residual oil dissolved in [D8]THF (0.3 mL) at 173 K (methanol/liquid
nitrogen bath). In a separate small flask, a weighted amount (12 mg,
0.1 mmol) of styrene oxide was dissolved in [D8]THF (0.2 mL) and the
resulting solution was then slowly added through a gas-tight syringe to
the solution of sBuLi. The resulting reaction mixture was then shaken
and immediately put in the NMR probe pre-cooled to 173 K. In the case
of a titration (or dilution) experiment, for each addition the sample was
ejected and placed in a 173 K bath, the Omnifit valve was opened, a de-
sired amount of co-solvent (or solvent) was added, and the desired NMR
experiments were run.
Preparation of (a,b-13C2)-styrene oxide. 3-Chloroperbenzoic acid (459 mg
of 75% mCPBA, 2 mmol) was added portionwise over a 15 min period
to
a
cold (ice bath) stirring solution of (a,b-13C2)styrene (200 mg,
1.89 mmol) in CH2Cl2 (15 mL). The reaction mixture was gradually
warmed to room temperature and stirred for additional 2 h; then, it was
diluted with hexane (30 mL) and the precipitate (3-chlorobenzoic acid)
removed by filtration. The filtrate was washed with a 1:1 mixture of 5%
aq NaHCO3 and 5% aq NaHSO3 (25 mL), then with aq NaOH 1m
(25 mL), and finally with brine and dried over anhyd Na2SO4. The sol-
vent was removed under reduced pressure and the crude product purified
by flash column chromatography (silica gel; hexane/Et2O 98:2, Rf =0.3)
to give (a,b-13C2)styrene oxide (176 mg, 76%). 1H NMR (600 MHz,
[D8]THF, 258C): d=7.26–7.33 (m, 5H; 5ArH), 3.75 (dm, 1J (C,H)=
175.2 Hz, 1H; CH), 3.01 (dm, 1J (C,H)=175.4 Hz, 1H; CH2), 2.65 ppm
(dm, 1J (C,H)=175.4 Hz, 1H; CH2); 13C NMR (150 MHz, [D8]THF,
258C): d=137.9 (d, 1J (C,C)=56.5 Hz, ipso-C), 129.1 (d, 2J (C,C)=
4.4 Hz; 2 CH), 128.6 (s, CH), 126.2 (d, 3J (C,C)=2.5 Hz; 2 CH), 52.4 (d,
1J (C,C)=27.9 Hz; CH), 51.2 ppm (d, 1J (C,C)=27.9 Hz; CH); MS
(70 eV): m/z (%): 122 (28) [M+], 121 (33) [M+ÀH], 93 (27), 92 (100)
[13CC6H7+] 91 (50), 90 (61). Optically active (S)-(a,b-13C2) styrene oxide
was prepared by hydrolytic kinetic resolution, likewise as reported.[53]
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Computational methods: Compounds were optimised at the B3LYP/6–
31+G(d) level of theory using Gaussian 98.[78] Single-point energy calcu-
lations were also performed at the B3LYP/6–311+GACHTNUTRGNEUNG(d,p)//B3LYP/6–31+
G(d) level of theory. All geometries were characterised as minima on the
potential-energy surface by using the sign of the eigenvalues of the force-
constant matrix from a frequency calculation. NMR chemical shielding
tensors were calculated at the B3LYP/6–311+G
ACHTUNGTREN(NUNG d,p)//B3LYP/6–31+
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luenga, J. Org. Chem. 2005, 70, 5852—5858, and references therein;
G(d) or B3LYP/6–311+G(2d,p)//B3LYP/6–31+G(d) levels of theory by
AHCTUNGTRENNUNG
using the GIAO approach as implemented in Gaussian. TMS in Td sym-
metry was used as a reference substance for the chemical shielding calcu-
lations. The figures of molecular structures were generated by using the
Chemcraft program (http://www.chemcraftprog.com).
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Carbenoid Chemistry
FULL PAPER
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[30] In the free lithium salt of the dimer 4c, the positive charge on lithi-
um is reduced (+0.87) compared to that found in the monomer 2a
(+0.91). Simultaneously, the negative charge in 4c is more localised
(À0.33) on Ca compared to that observed in the monomer 2a
(À0.30), while the negative charge on the oxirane oxygen and Cb
atom is reduced (see the Supporting Information).
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[32] As an estimate of the energy difference between structures with
[16] Lithiated styrene oxide
2 showed a lifetime in a macro batch
À
broken and closed C Li bonds, the C-Li-O core of the solvated
system, below À908C in THF and in the presence of three equiva-
lents of TMEDA, of only 30 min before decomposition takes place,
whereas lithiated 3-methyl-2-phenyloxiranes 3, under the same con-
ditions, proved to be chemically stable for at least 2 h.
dimers were frozen and the solvent removed. Optimisation of the
remaining atoms was performed and the energy compared to the
fully relaxed dimers 4a–d. It was found that the fully relaxed struc-
tures were 3–4 kcalmolÀ1 more stable. An additional energy analysis
was performed, in which the C-Li-O core of the unsolvated dimers
4a–d were frozen and the solvent and the remaining atoms were op-
timised. These structures were now found to be 4–8 kcalmolÀ1
[17] In the present paper the adjective “carbenoid” is used to describe
any carbene-like reactivity of an oxiranyllithium as it was introduced
for the first time by: L. Friedman, H. Shechter, J. Am. Chem. Soc.
1959, 81, 5512–5513; according to G. L. Closs, R. A. Moss, J. Am.
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behaviour, that is a nucleophilic as well as an electrophilic reactivity
according to the employed experimental conditions.
higher in energy than the fully optimised ([4aACTHNUGTRENNUG(thf)2]–[4dACHTUGNTNER(NUGN thf)2]). The
energy cost of 3–4 kcalmolÀ1 to elongate the C Li bonds is thus
compensated by the better THF solvation for such structures.
[33] W. Bauer, P. von R. Schleyer in Advances in Carbanion Chemistry,
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À
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[36] Lowering further the temperature of a 0.2m [D8]THF sample of
lithiated styrene oxide, solution viscosity considerably increased just
below 170 K, because of the closeness of the freezing point of the
solution. It is also worth noting that in the presence of a less polar
solvent such as [D10]Et2O a precipitate formed in the NMR tube
even at 173 K most probably because of low reagent solubility.
Therefore, all NMR experiments were run at 173 K employing
[D8]THF as the solvent system of choice.
[37] It has been reported (R. A. Gossage, J. T. B. H. Jastrzebski, C.
van Koten, Angew. Chem. 2005, 117, 1472–1478; Angew. Chem. Int.
Ed. 2005, 44, 1448–1454) that when a “stable” heteroaggregate, ki-
netically inert to further reaction with the starting material, forms
during a metalation reaction it generally tends to lower the yield of
the final adduct after “quenching” of the reaction mixture with an
electrophilic source; this drawback cannot be overcome even in the
presence of an excess of the same organolithium. NMR and experi-
mental data (ref. [14]) showed that just 1.2 equivalents of sBuLi
proved to be sufficient to promote a complete consumption of the
starting oxirane providing at the same time an almost quantitative
a-deuteration of lithiated styrene oxide.
[19] As a validation of the choice of basis set, 2 was also optimised at
the B3LYP/6-311+GACTHNUTRGNEU(GN d,p) level of theory. The average of the differ-
ences in bond distances at the two different levels was found to be
very small (0.003 ꢃ, see also Table S3 in the Supporting Informa-
tion). Thus, a geometry optimisation using the smaller basis set
seems to be sufficient.
[20] A. E. Reed, R. B. Weinstock, F. Weinhold, J. Chem. Phys. 1985, 83,
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[21] A number of NMR studies on several a-benzyl carbanions have
shown that the signal for the ipso-carbon atom is low-field shifted
with respect to the corresponding position in the neutral precursor,
showing a decrease of p- electron density and, therefore, a net posi-
tive charge in the anionic system: a) A. Abbotto, S. Bradamante, A.
Facchetti, G. A. Pagani, J. Org. Chem. 1999, 64, 6756–6763; b) A.
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[22] This value is obtained by dividing the total negative charge of the
phenyl ring by that of the total organic residue (Ph+Ca +Cb +
[38] For leading references to structural studies of RLi/R’OLi mixed ag-
gregates, see: a) reference [28b]; b) R. D. Thomas, H. Huang, J. Am.
Chem. Soc. 1999, 121, 11239–11240; c) G. T. DeLong, D. K. Pan-
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Corley, M. F. Huntington, E. J. J. Grabowski, J. F. Remenar, D. B.
Collum, J. Am. Chem. Soc. 1998, 120, 2028–2038.
O
oxirane +corresponding hydrogen atoms); the latter value (e.g.,
À0.91 in the tri-solvated species) can also be obtained by subtracting
from the charge of the system without molecules of solvent (À0.06)
the charge on lithium (+0.85).
[23] A. Abbotto, A. Streitwieser, P. von R. Schleyer, J. Am. Chem. Soc.
1997, 119, 11255–11268.
Chem. Eur. J. 2009, 15, 7958 – 7979
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V. Capriati, S. Florio et al.
[39] Surprinsingly, a literature search failed to reveal any systematic
NMR spectroscopic study of mixed aggregates derived from sBuOLi
and sBuLi in polar solvents. Indeed, very recently, only computa-
tional studies of mixed nBuLi/Li-N-methyl-2-pyrrolidine methoxide
aggregates in both hexane and THF (H. K. Khartabil, P. C. Gros, Y.
Fort, M. F. Ruiz-Lꢆpez, J. Org. Chem. 2008, 73, 9393–9402) and of
sBuLi with chiral lithium alkoxides in THF (L. M. Pratt, O. Kwon,
T. C. Ho, N. V. Nguyen, Tetrahedron 2008, 64, 5314–5321) have
been reported.
transversal (T2) relaxation times. As a consequence, the transverse
magnetisation arising from broad signals may be completely lost
during the preparation delays of the HMQC pulse sequence due to
relaxation through T2, so that no correlations will be finally ob-
served. This effect will be amplified as the temperature is decreased
(see: G. Fraenkel, J. H. Duncan, J. Wang, J. Am. Chem. Soc. 1999,
121, 432–443). As a precaution to minimise losses of magnetisation
along the pulse sequence, the short delay usually inserted between
the final 13C pulse and the start of acquisition was eliminated. Be-
7
[40] Further investigations on sBuLi/sBuOLi mixtures are underway and
will be reported in due course.
cause of the higher receptivity of Li with respect to 13C (RCarbon
A
ACTHNUTRGNEUNG
RCarbon(13C)=1590) we decided to use 7Li detection; in this way,
[41] J. M. Catala, G. Clout, G. Brossas, J. Organomet. Chem. 1981, 219,
139–143.
there would also be the possibility to take advantage of shorter ex-
7
perimental time due to faster relaxation of Li versus 13C. When 13C
[42] a) S. Harder, J. Boersma, L. Brandsma, J. A. Kanters, A. J. M. Dui-
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8446–8448.
decoupling is omitted during the acquisition time (t2), heteronuclear
7Li,13C coupling will be effective during FID sampling, thereby lead-
ing to cross-peak splitting in F2. A low-power 1H decoupling was
also applied during t2.
[43] a) P. Beak, A. I. Meyers, Acc. Chem. Res. 1986, 19, 356–363; b) P.
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[56] Total experimental time, te, resulted to be 19.22 min. In this case, te
is mainly determined by the 7Li relaxation time, the sweep width in
F2 and the number of increments in F1. In a similar experiment, but
run on a racemic sample of [a,b-13C2]styrene oxide, the number of
increments was increased from 256 up to 512 employing also a D2 =
4 ms for a final te =1.17 h. However, the new 2D spectrum did not
show additional cross-peaks.
[57] Even if reductive alkylation reactions compete to some extent soon
after the lithiation process, most probably with concomitant elimina-
tion of Li2O as byproduct, it seems improbable that a lithium peak
may be associated to such a salt because of its complete insolubility
in THF. Commercial Li2O, indeed, proved to be completely insolu-
ble in THF. Moreover, addition of water to a suspension of Li2O in
THF leads to the dissolution of this salt and a peak at d=0.57 ppm
(referenced externally to 0.3m LiCl in [D4]MeOH) emerges in
7Li NMR spectrum. This peak most probably refers to LiOH be-
cause when a solution was prepared from commercial LiOH in
THF/H2O, a similar chemical shift value was observed. Therefore,
the peak at d=0.57 ppm might in principle be assigned to LiOH or
to alkoxides, as discussed in the main body of the paper.
[48] The two doublets at d=129.7 and 136.2 ppm were always detected
in the 13C NMR spectrum each time doubly 13C-enriched styrene
oxide was reacted with sBuLi.
[49] d=81.2 with 58.6; 81.6 (82.2) and 82.0 (82.5) with 58.8 and 58.9;
83.2 with 58.1; 83.8 with 62.0 (13C,13C-COSY); 74.7 with 59.2; 73.0
with 60.3 ppm.
[50] a) S. Schade, G. Boche, J. Organomet. Chem. 1998, 550, 381–395;
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[58] Concentration-dependent studies were frustrated by the very high
reactivity of 2. The only successful and feasible dilutions (in order to
obtain “homogeneous” samples to be compared) could only be per-
formed directly in the NMR tube by adding solvent. Any attempt to
pull a portion of the sample containing the oxiranyllithium up into a
syringe in order to dilute it more, led to a considerable quenching
and decomposition of the anion. That is why the “precious” sample
of optically active and doubly enriched styrene oxide was only dilut-
ed (in the NMR tube) up to a factor of 2. Isolated samples of race-
mic lithiated styrene oxide, prepared at higher dilution (up to
0.03m), showed that the various aggregates continued to compete
with the monomeric species; however, they were always in slow
equilibration on the NMR timescale.
[59] W. Bauer, J. Am. Chem. Soc. 1996, 118, 5450–5455.
[60] Similarly, a dimeric triple ion has recently been found to intercon-
vert slowly on the NMR timescale with both monomeric contact
and solvent-separated ion pairs; see reference [50b].
[61] An interesting case of diastereomeric ether solvates under slow ex-
change in dimethyl ether solution, in which lithium behaves as a
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[62] A case of
a
dimeric TMEDA-complexed 2-lithiobenzofuran, in
À
which a single C O bond is Li-bridged and a single lithium adopts a
pentacoordinate structure (the other one being tetracoordinate), has
been reported: S. Harder, J. Boersma, L. Brandsma, J. A. Kanters,
W. Bauer, R. Pi, P. von R. Schleyer, H. Schçllhorn, U. Thewalt, Or-
ganometallics 1989, 8, 1688–1696.
[55] In principle, with our special triple resonance probehead (with the
inner coil selectively tuned to 13C frequency and the outer coil tuna-
ble between the frequencies of 7Li (see the Experimental Section)
such a two-dimensional NMR shift correlation, based on scalar
spin–spin coupling, may be performed. However, one of the main
drawbacks to take into account in setting up this type of experiment
is related to the fast relaxation of 7Li which poses problems for the
[63] Interestingly, the carbenoid 1-ethoxy-1-lithioethene has been report-
ed to exist in the crystalline state as a self-assembled polymeric
chain, the asymmetric unit of which contains four molecules aggre-
gated to form a distorted cubic Li4C4 tetramer, while the remaining
two generate a second tetrameric aggregate: K. Sorger, W. Bauer,
7
7
line-width of the Li resonances; in fact, Li is a nucleus with a mod-
erate quadrupolar moment exhibiting short longitudinal (T1) and
7978
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Chem. Eur. J. 2009, 15, 7958 – 7979

Carbenoid Chemistry
FULL PAPER
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[64] A recent computational investigation performed on lithiated ethyl-
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and three diastereomeric tetramers, the latter characterised by an
higher distortion of their geometry compared to that of alkyllithium
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[72] In Table 1 is shown the calculated chemical shieldings for the free
and solvated monomer applying two different basis sets. It is ob-
served that the more flexible basis set, including two d-functions on
heavy atoms, gives a slightly better agreement with the experimen-
tally observed chemical shifts. However, the small difference be-
tween the methods encouraged us to use the smaller basis set in the
studies of the larger aggregates involving the dimer 4. The chemical
shift dependence on the level of geometry optimisation was also ex-
amined for compound 2. Only small differences could be observed,
Received: March 31, 2009
Revised: June 23, 2009
Published online: July 21, 2009
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7979