On the mechanism of the naphthalene-catalysed lithiation: The role of the naphthalene dianion

Article abstract of DOI:10.1016/S0040-4039(01)00512-3

Kinetic and distribution product studies on naphthalene-catalysed lithiation reactions of chlorinated precursors have shown the probable participation of a naphthalene dianion (dilithium naphthalene) as the very active electron carrier agent in the chlorine-lithium exchange process.

Full text of DOI:10.1016/S0040-4039(01)00512-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3455–3458
On the mechanism of the naphthalene-catalysed lithiation: the
role of the naphthalene dianion
Miguel Yus,* Raquel P. Herrera and Albert Guijarro
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99, E-03080 Alicante, Spain
Received 23 March 2001; accepted 26 March 2001
Abstract—Kinetic and distribution product studies on naphthalene-catalysed lithiation reactions of chlorinated precursors have
shown the probable participation of a naphthalene dianion (dilithium naphthalene) as the very active electron carrier agent in the
chlorine–lithium exchange process. © 2001 Elsevier Science Ltd. All rights reserved.
The use of lithium and a catalytic amount of an arene
as the electron carrier has become a useful procedure
for the preparation of organolithium compounds under
very mild reaction conditions.1 This lithiation method-
ology, compared to the use of a stoichiometric amount
of an arene,2 has the advantage of being a very clean
process with a simple work-up (not necessary to remove
a large amount of the arene) but, above all, the cata-
lytic version is far more reactive, so it is possible to
perform new lithiation reactions, which do not work
when a lithium–arene is used as lithiation agent.3 Thus,
it appears to be evident that different species take active
part in both lithiation processes. In the stoichiometric
version, it has been postulated and accepted that a
radical anion is the electron transfer (ET) agent, naph-
thalene and 4,4%-di-tert-butylbiphenyl (DTBB) being
the arenes most commonly used. This type of paramag-
netic compounds (LiC10H8 or LiDTBB) have been suc-
react as a base or as a nucleophile,10 but also as an ET
reagent,11 in the same way than its radical anion coun-
terpart. The study of this reactivity is interesting from a
fundamental point of view in order to clarify the gen-
eral dichotomy between an ET reaction and a nucleo-
philic substitution.
Dianion
Radical anion
Li
Li
Li
II (Li2C10H8)
I (LiC10H8)
In order to study the reactivity of the radical anion and
the dianion species, we used organic chlorides and
naphthalene as the arene. Employing competitive
kinetic techniques12 it is possible to measure accurately
the relative reaction rates by comparing simultaneously
the reactivity of the species I–IV with two different
organic halides (1- and 2-chlorooctane, 2-chloro-2-
methylheptane and chlorobenzene). As reactive anionic
species, the radical anion I [prepared with lithium and
naphthalene (1:1.1), green solution], and dianions II
[prepared with an excess of lithium and naphthalene
(5:1), purple solution when freshly prepared], III
(Li2C10H8·2TMEDA, from 1,4-dihydronaphthalene an
n-butyllithium, purple when freshly prepared) and IV
(as for II, but with 2 TMEDA, purple when freshly
prepared) were used. In a representative example, to a
mixture of 1-chlorooctane, 2-chlorooctane and a care-
fully weighed amount of dodecane (internal standard;
ca. 1:1:0.5, 0.01 M) was added a solution of lithium
cessfully
employed
for
chlorine–lithium4
and
sulphur–lithium5 exchange as well as for the reductive
opening of cyclic ethers.6 Over-reduction of the radical
anion species can be achieved by condensation of
potassium and naphthalene vapours,7 and apparently
by prolonged exposure of naphthalene to an excess of
lithium metal in THF.8 On the other hand, double
deprotonation of 1,4-dihydronaphthalene with n-butyl-
lithium and tetramethylethylenediamine (TMEDA)
affords Li2C10H8·2TMEDA as purple crystals.9 The
reactivity of this diamagnetic species, which can be
formulated as shows structure II compared with the
radical anion I, is almost unknown: in fact, it could
Keywords: arenes; catalysts; electron transfer; lithiation; organometal-
lic compounds.
* Corresponding author. Fax: +34-96-5903549; e-mail: yus@ua.es
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00512-3

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M. Yus et al. / Tetrahedron Letters 42 (2001) 3455–3458
naphthalene (LiC10H8, I) in THF at 0°C in small por-
tions. A sample of this reaction mixture was taken after
each addition and hydrolysed (phosphate buffer, 0°C)
and submitted to quantitative GLC analysis. After
determination of the concentration of both organic
pathways for the dianion, such as a back approach to
the halide in a SN2 transition state metallation type [e.g.
ferrates,13 or Co(I) reagents,14 which would display a
primary>secondaryꢀtertiary alkyl or aryl chlorides
reactivity profile] or the intervention of an ‘ate’ transi-
tion state or an intermediate (e.g. alkyllithiums15 and
presumably dialkylmagnesium reagents16 would afford
a different profile: arylꢀprimary>secondary>tertiary
alkyl chlorides).
chlorides a relative reaction rate12 of k2-octylCl/k1-octylCl
=
0.91 was obtained. The same procedure was repeated
for all pairs of organic chlorides and the species I–IV
(clear solutions without any lithium metal), the result-
ing reproducible relative rates being referred to the
primary chloride. The obtained results are summarised
in Fig. 1, where reactivity profiles for all four reagents
are essentially identical. According to these data,
dilithium naphthalene behaves as an ET reagent towards
organic chlorides, being indistinguishable with lithium
naphthalene as far as the reactivity profiles are
concerned.
The generally accepted mechanism for the reaction of
’
arene radical anions (e.g. C10H8−) is in principle, appli-
cable to naphthalene dianion (Scheme 1, Eqs. (1)–(3)).
It is not likely that the radical anion present in the
reaction media can compete with the dianion for
organic chlorides when both are present in similar
concentrations based on both (a) less favorable reduc-
tion potentials,17 and (b) dissimilar electronic configura-
tions of reactants criteria. Neither is the SN2
competence versus ET for organic chlorides as it can be
inferred from the reactivity profiles (Eq. (1)). In the
subsequent step, both reducing agents can in principle
participate (Eq. (2)), the coupling of R and the radical
anion being most likely the source of coupling by-prod-
ucts (isomeric RC10H9, R2C10H8 and dimers) (Eq. (3)).
Regarding the mechanism of the lithiation, there is no
selectivity for the structure of the organic halide in the
process as it would be expected from an outer sphere
ET in the determining step of the reaction.12 This is the
mechanism of reaction for most radical anions, such as
I, with organic halides. The resulting flat profiles dis-
played discard other possible metallation mechanistic
Figure 1. Reactivity profiles of naphthalene radical-anion (I) and dianions (II–IV) in their reactions with organic chlorides. Each
relative rate has been obtained by evaluation of the slope by linear regression analysis of plots representing the decay of the
concentration of both chlorides,12 and are arbitrarily referred to 1-chlorooctane. Each of these plots contained 5–8 points and
were linear to greater than 90% consumption of the reacting chlorides (first order reactions with respect to the alkyl chloride), the
regression coefficients being >0.995 in all cases.

M. Yus et al. / Tetrahedron Letters 42 (2001) 3455–3458
3457
kET
•–
R• + X–+ C10H8
C10H8–2+ RX
kS 2
N
(1)
RC10H8–+ X–
//
k2
•– (or –2)
(or •–)
(2)
(3)
R• + C10H8
R– + C10H8
k3
–
•–
RC10H8
R• + C10H8
Scheme 1.
The k2/k3 ratio is a key parameter of the process when
the aim is to maximise the formation of R−. For radical
anions, the ratio k2/k3 seems to be dependent on the
standard reduction potential of the arene, the most
negative ones having the higher k2/k3 ratios, resulting in
higher yields of carbanionic species.18 This trend is
manifested by the dianion as small but reproducible
better yields in the lithiation process using II compared
to I.
At this stage, a study of the distribution of products
was undertaken to obtain information about the evolu-
tion of the radical species initially formed from the ET
step. As expected, further reduction to afford organo-
lithium compounds is the main reaction outcome for
dianions as well as for the radical anion. To demon-
strate that, the reaction of I–IV with 1-chlorooctane
was carried out in THF at −60°C (temperature at which
crystalline III showed adequate solubility) followed by
reaction with chlorotrimethylsilane or pivalaldehyde as
electrophilic reagents and final hydrolysis, giving
trimethyl octyl silane or 2,2-dimethyl-3-undecanol,
respectively The first step was carried out with an
excess of lithiating reagent (4:1 molar ratio) and was
monitored until the concentration of the starting mate-
rial dropped below detection limits (<0.01%), then an
excess of the electrophilic reagent was added, the reac-
tion was allowed to warm up slowly to 0°C and was
hydrolysed as before. Quantitative analysis of the reac-
tion products afforded comparable distribution of
major products for both I and II (reactions in the
absence of TMEDA), reagent II invariably giving
slightly better yields that I for the aforesaid reasons.18
Yields were found to be very similar specially for III
and IV (reactions in the presence of TMEDA) (Fig. 2).
These last results confirm how close is the nature of the
species generated after exposure of naphthalene to an
excess of lithium, and pure dilithium naphthalene.
Figure 2. Distribution of products corresponding to the reac-
tion of 1-octylchloride with the lithiating reagents I–IV and
capture of 1-octyllithium with (a) TMSCl or (b) t-BuCHO.
Yields of the products were determined by quantitative GLC
using pure isolated products in the determination of response
factors, and were averaged for 4–5 runs.
dihydronaphtalene (47%) and 1-nonyl-1,2-dihydro-
naphtalene (36%) as major products.
Some conclusions can be drawn from the present work.
The answer to the original question whether dianions
are or are not active part in the mechanism of the
arene-catalysed lithiation, for which organic chlorides
are their natural substrates, has now been addressed.
Dilithium naphthalene arises as a formal lithiating
agent in its reaction with organic chlorides, and pre-
sumably with other functional groups,19 displaying an
outer sphere ET reactivity profile in its interaction with
these acceptors, excluding alternative mechanisms of
halogen–lithium exchange. Endowed with a higher
redox potential than its radical anion counterpart, its
reactivity spectrum is broadened and so is the range of
substrates suitable for lithiation. Hence, we can state
that the trivial mechanism of lithiation involving radical
anions is not the only operative in arene catalysed
lithiations, a more reduced species, i.e. the dilithium
salt of the arene or dianion may be responsible instead
for the increased reactivity displayed by the mixture.
Advantages of arene dianions in lithiation processes
versus arene radical anions inevitably comes from the
higher reduction potential of the corresponding redox
pairs, which broaden the scope of current lithiating
agents to functional groups reducible only with
difficulty. Studies to implement this hypothesis to a real
case are currently underway. Preliminary results show
that alkyl fluorides readily react with solutions contain-
ing dilithium naphthalene (II or III). Thus, for instance,
the reaction of 1-fluorononane with II at 0°C is com-
pleted in 10 min. After hydrolysis with water it afforded
nonane (7%) and a separable mixture of 1-nonyl-1,4-
Acknowledgements
This work was financially supported by the DGES from
the Spanish Ministerio de Educacio´n y Cultura (MEC)
(project no. PB-97-0133).

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M. Yus et al. / Tetrahedron Letters 42 (2001) 3455–3458
10. (a) Korte, W. D.; Cripe, K.; Cooke, R. J. Org. Chem.
References
1974, 39, 1168; (b) Sommer, L. H.; Korte, W. D. J. Org.
Chem. 1970, 35, 22.
1. (a) Yus, M. Chem. Soc. Rev. 1996, 96, 155; (b) Ramo´n,
D. J.; Yus, M. Eur. J. Org. Chem. 2000, 225.
2. Holy, N. L. Chem. Rev. 1974, 74, 243.
11. For a number of studies concerning the competition
between ET and SN2, see: (a) Daasberg, K.; Christensen,
T. B. Acta Chem. Scand. 1995, 49, 128; (b) Huang, Y.;
Wayner, D. D. M. J. Am. Chem. Soc. 1994, 116, 2157.
12. (a) Guijarro, A.; Rieke, R. D. Angew. Chem., Int. Ed.
1998, 37, 1679; (b) Guijarro, A.; Rosenberg, D. M.;
Rieke, R. D. J. Am. Chem. Soc. 1999, 121, 4155.
13. (a) Collmann, J. P.; Hegedus, L. S. In: Principles and
Applications of Organotransition Metal Chemistry; Uni-
versity Science Books: Mill Valley, CA, 1980; Chapter 4;
(b) Collman, J. P.; Finke, R. G.; Cawse, J. N.; Brauman,
J. I. J. Am. Chem. Soc. 1977, 99, 2515.
3. See, for instance: Almena, J.; Foubelo, F.; Yus, M. J.
Org. Chem. 1994, 59, 3210.
4. See, for instance: (a) Freeman, P. K.; Hutchinson, L. L.
J. Org. Chem. 1980, 45, 1924; (b) Ramo´n, D. J.; Yus, M.
J. Org. Chem. 1991, 56, 3825.
5. (a) For a review, see: Cohen, T.; Bhupathy, M. Acc.
Chem. Res. 1989, 22, 152; (b) For a recent account, see:
Cheng, D.; Zhu, S.; Liu, X.; Norton, S. H.; Cohen, T. J.
Am. Chem. Soc. 1999, 121, 10241.
6. (a) For a review, see: Yus, M.; Foubelo, F. Rev. Het-
eroat. Chem. 1997, 17, 73; (b) First account: Bartmann,
E. Angew. Chem., Int. Ed. Engl. 1986, 25, 653; (c) See,
also: Dorigo, A. E.; Houk, K. N.; Cohen, T. J. Am.
Chem. Soc. 1989, 111, 8976; (d) Cohen, T.; Jeong, J.-H.;
Mudrik, B.; Bhupathy, B.; Awan, M. M. A. J. Org.
Chem. 1990, 55, 1528; (e) Mudrik, B.; Cohen, T. J. Org.
Chem. 1989, 54, 5657; (f) Mudrik, B.; Cohen, T. J. Am.
Chem. Soc. 1991, 113, 1866.
14. (a) Zhou, D. L.; Walder, P.; Scheffold, R.; Walder, L.
Helv. Chim. Acta 1992, 75, 995; (b) Schrauzer, G. N.;
Deutsch, E. J. Am. Chem. Soc. 1969, 91, 3341.
15. Wakefield, B. J. Organolithium Methods; Academic Press:
London, 1988.
16. Boymond, L.; Rottla¨nder, M.; Cahiez, G.; Knochel, P.
Angew. Chem., Int. Ed. 1998, 37, 1701.
17. This is not invariably a guarantee for faster ET reactions:
7. Brandes, K. K.; Gerdes, R. J. J. Phys. Chem. 1967, 71,
508.
8. Smith, J. J. Am. Chem. Soc. 1965, 87, 656.
9. Brooks, J. J.; Rhine, W.; Stucky, G. D. J. Am. Chem.
Soc. 1972, 94, 7346.
Marcus, R. A. Pure Appl. Chem. 1997, 69, 13.
18. Fuhlendorff, R.; Occhialini, D.; Pedersen, S. U.; Lund,
H. Acta Chem. Scand. 1989, 43, 803.
19. For reviews, see: (a) Refs. 1 and 6b; (b) Guijarro, D.;
Yus, M. Recent Res. Devel. Org. Chem. 1998, 2, 713.
.
.