The cocondensation reaction of lithium atoms and anisole: An experimental and theoretical study of the reaction pathway

Article abstract of DOI:10.1016/j.jorganchem.2004.12.016

The cocondensation reaction of lithium atoms and pure anisole leads to an ortho CH activation and the formation of lithium hydride. This simple two-component system allows the investigation of the reaction mechanism with included donor molecules. Therefore two anisole and one dilithium molecule, which was identified in an earlier spectroscopic study, were considered for the reaction pathway calculations. Firstly, two intermediates can be found along the reaction pathway, which show the reaction before and after the critical CH activation step. Secondly, a low-lying transition state can be identified, which allows the carbon hydrogen bond to be broken with an activation energy of less than 20 kcal/mol instead of more than 100 kcal/mol, if a free radical mechanism is employed. All calculations were performed at the B3LYP/6-31G** level of theory.

Full text of DOI:10.1016/j.jorganchem.2004.12.016

Journal of Organometallic Chemistry 690 (2005) 1511–1522
www.elsevier.com/locate/jorganchem
The cocondensation reaction of lithium atoms and anisole:
an experimental and theoretical study of the reaction pathway
*
Oscar Mendoza, Laurence P. Cuffe, Franz-Josef K. Rehmann, Matthias Tacke
Department of Chemistry, Centre for Synthesis and Chemical Biology (CSCB), Conway Institute of Biomolecular and Biomedical Research,
University College Dublin, Belfield, Dublin 4, Ireland
Received 28 October 2004; accepted 17 December 2004
Available online 7 February 2005
Abstract
The cocondensation reaction of lithium atoms and pure anisole leads to an ortho CH activation and the formation of lithium
hydride. This simple two-component system allows the investigation of the reaction mechanism with included donor molecules.
Therefore two anisole and one dilithium molecule, which was identified in an earlier spectroscopic study, were considered for the
reaction pathway calculations.
Firstly, two intermediates can be found along the reaction pathway, which show the reaction before and after the critical CH
activation step. Secondly, a low-lying transition state can be identified, which allows the carbon hydrogen bond to be broken with
an activation energy of less than 20 kcal/mol instead of more than 100 kcal/mol, if a free radical mechanism is employed. All cal-
culations were performed at the B3LYP/6-31G** level of theory.
Ó 2004 Elsevier B.V. All rights reserved.
Keywords: Lithium atoms; Metal vapour synthesis; CH activation; Reaction pathway calculation; DFT
1. Introduction
One of the key intermediates in this reaction is a Li2–
benzene p-complex. This complex is capable of undergo-
ing a two-electron transfer from the Li2 to the lowest
unoccupied molecular orbital (LUMO) of the aromatic
ring, resulting in the activation of the aromatic C–H
bond.
The activation of carbon–hydrogen bonds has been a
major topic of research for the last 30 years [1–3]. Earlier
reports involving lithium atoms [4–6] showed that they
are able to activate aromatic hydrocarbons in the pres-
ence of THF selectively under cocondensation condi-
tions at 77 K. This resulted in the direct synthesis of
aryl-lithium compounds on a synthetic scale.
Li
cocond.
77K
Ph
H
Li Li
2 Li(g) + 4 PhH(g)
PhH
LiH(s) + PhLi(s)
Li
The work has been expanded to +I substituted (CMe3,
SiMe3, o- and m-Xylene) and donor substituted (OMe,
NMe2, SMe) benzene derivatives recently [7]. In the case
of anisole a selective C–H bond activation in the presence
of THF was found to occur in the ortho position. The
aim of this paper is to understand the reaction mecha-
nism occurring in a cocondensation reaction of lithium
atoms and pure anisole, when THF is not present.
cocond.
77K
8 Li(g) + 4 PhH(g) + 4 THF(g)
Li(THF)
+ 4 LiH(s)
4
*
Corresponding author. Tel.: +353 17168428; fax: +353 17162127.
E-mail address: matthias.tacke@ucd.ie (M. Tacke).
0022-328X/$ - see front matter Ó 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2004.12.016

1512
O. Mendoza et al. / Journal of Organometallic Chemistry 690 (2005) 1511–1522
2. Experimental study
O
O
Li
cocond.
Many aromatic compounds, as benzenes or heterocy-
cles, show C–H activation when cocondensed with lith-
ium atoms at 77 K. The presence of THF molecules was
shown to be an essential part of the cocondensation
reaction.
77K, Li(g)
(g)
Scheme 2. Cocondensation reaction of lithium atoms with anisole at
77 K.
Previous studies showed the cocondensation reaction
of lithium and ÀI substituted benzenes compounds, as
anisole, in the presence of THF. For all the cases, the
observed lithiated compound was shown to be ortho
lithiated.
In this study the ortho position where the C–H activa-
tion occurs was blocked. For this propose the reactions
of 2-methyl anisole and 2,6-dimethyl anisole were car-
ried out under cocondensation conditions. Both showed
two lithiated products from the cocondensation experi-
ment: substituted phenyl lithium was found as a result
of a C–H activation and lithium phenolate as a result
of a C–O activation [8,9].
In the case of one ortho position blocked as in 2-
methyl anisole, the C–H activation was found in the sec-
ond ortho position. However for 2,6-dimethyl anisole
the activation was found in the para position with re-
spect to the methoxy group and it is shown in Scheme 1.
In order to study the importance of a donor solvent
in these reactions, a cocondensation reaction of anisole
and lithiums atoms was carried out without the presence
of THF as additional oxygen donor ligand. Also a lith-
iated product was observed and identified as 2-lithio ani-
sole (Scheme 2).
the presence of THF [5]. The DFT study of the reactions
showed reaction pathways where different intermediates
were identified. The formation of a dilithium molecule
and its interaction with the aromatic system of anisole
has been the main topic.
As reported previously, the benzene derivate anisole
shows a C–H activation reaction when cocondensed
with lithium atoms without the involvement of THF
as solvent. The aim of this work is to identify, by calcu-
lation, plausible intermediate species for the anisole
cocondensation reaction of lithium atoms without
THF, and thereby identifying the local minima and
transition states in all the possible pathways. Calcula-
tions were performed using GAUSSIAN-98 [14] and the
B3LYP DFT functional [15–18] in combination with
the 6-31G** [19–22] basis set.
Initially, one anisole molecule interacting with the dil-
ithium species was considered. The C–H activation in-
volves several steps and several intermediates can be
identified in this pathway reaction. Once the Li2 species
is formed from two lithium atoms, its coordination with
the aromatic compound gives three possible first stable
intermediates (1a–c) in exothermic reactions (Scheme
3). In this intermediate the dilithium molecule forms a
complex with the anisole in three different ways: a r-
complex with the oxygen (1b), a p-complex with the aro-
matic ring (1c) and both r- and p-complex at the same
time (1a) (Scheme 3). The formation of 1a could be con-
sidered as a direct formation from dilithium and anisole
or through the formation of a previous intermediate 1b
or 1c.
3. Theoretical study
Theoretical studies and thermodynamic details for
organolithium species have been reported previously
[10–13]. A simple example shows the reaction of benzene
and its derivates with lithium atoms, which under cocon-
densation conditions are able to activate C–H bonds in
Li
O
O
O
Li
cocond.
+ LiH
+ LiMe
77K, Li(g)
(g)
40%
O
60%
Li
O
O
cocond.
+ LiH
+ LiMe
77K, Li(g)
(g)
Li
24%
76%
Scheme 1. Cocondensation reaction of lithium atoms with 2-methyl anisole and 2,6-dimethyl anisole at 77 K in presence of THF.

O. Mendoza et al. / Journal of Organometallic Chemistry 690 (2005) 1511–1522
1513
E
O
2Li(g)
+
Li
H
-24.6 kcal/mol
O
Li
O
TS0
-1.3 kcal/mol
-9.1 kcal/mol
Li2
+
Li
Li
O
+9.9 kcal/mol
1a
+7.8 kcal/mol
Li
O
Li
1c
Li
-12.5 kcal/mol
Li
+11.2 kcal/mol
O
Li
O
Li
H
O
1b
Li
Li
1a
2
Reaction coordinates
Scheme 4. C–H activation step in the pathway involving one anisole
molecule.
Scheme 3. Formation energies for the first three intermediates of the
reaction.
The three first intermediate are stable structures and
show a local minimum in energy. Formation involves
exothermic reaction for all of them, however r-coordi-
nation shows a more exothermic reaction enthalpy of
À12.5 kcal/mol.
The reaction mechanism shows intermediates com-
pounds optimised as a local minimum, however this is
not an equilibrium reaction and the species have addi-
tional energy due to the high exothermic first step (for-
mation of dilithium). This energy added to species 1b
could enable the presence of 1a.
The next step on the reaction pathway is the activa-
tion of the C–H bond. As previously reported [7], this
step involves the double electron transfer from the inter-
mediate 1a–c to the LUMO of the aromatic ring and this
results in the insertion of the Li2 into the C–H bond. The
step involves an endothermic reaction step to reach a
transition state, and then an exothermic process leads
to a second intermediate 2. For this purpose 1a is con-
sidered as the first intermediate because it is so closely
related to the structure of the calculated transition state.
In order to reach the transition state from 1a, the ortho
C–H bond on the anisole molecule is elongated and
moves through the lithium–lithium bond. The Li–Li dis-
tance widens as well and allows the formation of a C–
Li2–H four-membered ring in a third intermediate
(Scheme 4).
On this pathway, the transition state (TS0) identified
shows only one negative frequency of À513 cmÀ1. This
corresponds to the hydrogen moving across the lith-
ium–lithium bond. Fig. 1 shows the numbering scheme
that is used in Tables 1 and 2.
During this activation, an elongation on the C–H
bond from 108.7 in 1a to 298.6 pm in 2 occurs. In the
transition state the C–H bond is widened to 137.5 pm
(Table 1), while the Li–Li distance is elongated from
285.8 pm in 1a to non-bonding 355.3 pm in the transi-
tion state (Table 2).
Fig. 1. Gaussview plot of the transition state TS0 involving one anisole
molecule.
formed. In this species the p-interaction of the ring with
the second lithium disappears and a C–Li sigma bond is
formed instead (Scheme 5). This is an exothermic step of
À7.5 kcal/mol and leads to a structure characterised by
the electron deficient C–Li2–H ring.
The last step in this process is the formation of solid
LiH and 2-lithio anisole, which is characterised by X-ray
crystallography [23]. The solid-state structure of this
compound consists of four lithium atoms arranged in
a slightly distorted tetrahedron, which binds to the four
anisyl groups. The anionic carbon atom of an anisyl
group is bonded to three lithium atoms. An asymmetry
of this structure comes from the fact that two lithium
atoms have only one O–Li contact and the other two
have either two or none (Fig. 2).
The most important distances of the crystal and
calculated DFT structure are presented in Table 3.
Both data sets show very similar bond length, only
Li2–C12 and Li4–C42 show larger differences than
10 pm.
To carry out the calculation of the thermodynamical
data of the last step, two considerations are necessary.
All the calculations and thermodynamical values have
been calculated at B3LYP/6-31G** level, however the
After the activation of the C–H bond leading to 2 one
more intermediate (3) is found before the final product is

1514
O. Mendoza et al. / Journal of Organometallic Chemistry 690 (2005) 1511–1522
Table 1
Selected bond distances and negative frequency of the calculated
structure of the transition state (TS0)
TS0
(pm)
C(1)–Li(2)
C(2)–Li(2)
C(3)–Li(2)
C(4)–Li(2)
C(5)–Li(2)
C(6)–Li(2)
C(1)–Li(1)
C(1)–H
220.3
217.8
216.4
220.7
243.0
242.7
194.5
137.5
À513 cmÀ1
m
Table 2
Selected interatomic distances for the calculated structures of 1a, TS0
and 2
1a (pm)
TS0 (pm)
2 (pm)
C(1)–H
Li(1)–Li(2)
O–Li(1)
108.7
285.8
201.6
227.9
225.2
137.5
355.3
196.5
194.5
220.3
298.6
260.1
209.3
207.3
228.5
Fig. 2. Gaussview plot of tetrameric 2-lithio anisole (Li–C bonds have
been omitted for clarity).
Li(1)–C(1)
Li(2)–C(1)
Table 3
Selected bond distances for tetrameric 2-lithio anisole from the crystal
and the DFT structure
Li
Li
-7.5 kcal/mol
Bond length (pm)
crystal structure
Bond length (pm)
DFT calculation
O
Li
O
Li
H
H
Li(1)–C(22)
Li(1)–C(12)
Li(1)–C(42)
Li(2)–O(1)
Li(2)–C(12)
Li(2)–C(22)
Li(2)–C(32)
Li(3)–O(2)
Li(3)–C(22)
Li(3)–C(32)
Li(3)–C(42)
Li(4)–O(3)
Li(4)–O(4)
Li(4)–C(12)
Li(4)–C(32)
Li(4)–C(42)
Li(1)–Li(2)
Li(1)–Li(3)
Li(1)–Li(4)
Li(2)–Li(3)
Li(2)–Li(4)
Li(3)–Li(4)
218
221
223
193
225
220
213
195
244
219
222
193
201
226
251
240
250
259
262
260
265
265
218.0
216.4
216.1
193.7
243.6
220.1
220.4
196.0
245.8
222.6
219.9
196.1
196.4
224.9
244.3
262.9
250.9
250.8
263.6
256.2
268.0
265.6
3
2
Scheme 5. Formation of intermediate 3 in a reaction involving one
anisole molecule.
vibrational energies for the tetrameric lithium anisole
structure was computed at B3LYP/3-21G* level of the-
ory. Experimental values were included for the forma-
tion of solid LiH and the Li2 molecule (Scheme 6).
The electron deficient Li2 molecule will accept elec-
tron density from the aromatic anisole to form an ex-
pected r-complex 1b or unusual p-complex 1c. The
next mechanistic step is crucial and involves the double
electron transfer from the lithium complex to the
LUMO of the aromatic ring.
Studies of the charge distribution in TS0 and 1a were
carried out and are presented in Table 4. Intermediate
1a shows a small positive charge (0.12 au) on the Li–
Li while a negative is found on the aromatic ring. The
electronic distribution probe that the dilithium is al-
ready transferring electrons to the aromatic system
occupying the LUMO of the ring. The calculated struc-
ture 1a shows a negligible difference in energy when cal-
culated in a triplet or singlet state and makes them both
possible intermediates.
on TS0 shows a larger positive charge on both lithium
atoms and also a larger negative charge on the anisole
molecule, which is distributed between the aromatic ring
and the methoxy group.
When a second molecule of anisole is considered, the
situation turns out to be more complicated and more
pathways must be considered. The formation of the dil-
ithium species followed by the coordination with one
After the formation of (1a–c) by exothermic reaction
steps, the activation of the CH bond occurs and leads to
2 through the transition state. The charge distribution

O. Mendoza et al. / Journal of Organometallic Chemistry 690 (2005) 1511–1522
1515
O
the other two are formed from r- or p-coordination
with the other lithium. Scheme 7 shows the most stable
first intermediates for the four different pathways.
O
-24.6 kcal/mol
2Li +
Li2
+
-12.5 kcal/mol
-1.3 kcal/mol
3.1. Pathways 1 and 2
O
Li
Li
Li
O
Li
H
ol
TS 0
ol
+11.2 kcal/mol
When a second anisole donor is forming a r-com-
plex, two pathways can be considered (pathways 1 and
2). A necessary first intermediate would be formed by
the dilithium molecule r- and p-bonded with one anisole
(1a) and the other anisole molecule r-coordinated to
one of the two lithium atoms (4a and 6a) as shown in
Scheme 8.
Both species are found to be stable intermediates and
their formations involve an exothermic step of À11.7
and À12.3 kcal/mol respectively, when synthesised from
1a and one anisole molecule.
(+9.9 kcal/mol)
-27.6 kcal/mol
Li
O
Li
H
Li
O
Li
-7.5 kcal/mol
B3LYP/6-31G**
-31.2 kcal/mol 1/4 Li4 (C6H4OMe)4 + LiH(s)
Li
H
O
Li
Scheme 6. Reaction pathway involving one anisole molecule and two
lithium atoms.
However, the necessary intermediates 4a and 6a
could be formed via 4b and 6b respectively due to their
stability (Scheme 8). Once the r-complex 1b is formed,
the second anisole makes a new r-coordination (4b
and 6b). Then the lithium–lithium bond approaches
the aromatic ring. The aryl structure and one lithium
coordinate and a p-complex are formed (4a and 6a).
This is an endothermic reaction step and needs 8.6 or
5.4 kcal/mol respectively; the result is presented in
Scheme 9. However as explained on one anisole mecha-
nism, this is not an equilibrium reaction and the species
could have extra energy and would not be in a local
minimum.
Table 4
Charge distribution for the structure of 1a and TS0
1a
TS0
Li(1)
Li(2)
O
+0.019
+0.103
+0.048
À0.463
+0.047
+0.226
À0.360
À0.064
+0.011
+0.654
+0.415
À0.502
À0.774
+0.274
À0.092
À0.372
À0.288
+0.335
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
anisole molecule is found as well. However, at this point
the second anisole molecule is coordinated to the Li–Li–
anisole intermediate. For this purpose the structure ele-
ment represented by 1b and a further anisole molecule
are considered to form a new intermediate.
Once one anisole molecule is coordinated to the dili-
thium species, the interaction with the second anisole
takes place. Four different possibilities are found for this
interaction: two possibilities arise from r- or p-coordi-
nation with one lithium in the dilithium species, and
The next step is the activation of the C–H bond. For
this reaction step the C–H bond elongates when it ap-
proaches the Li–Li bond, which is stretched as well while
the hydrogen crosses the bond. Both transition states
(TS1, TS2) have been characterised by one negative fre-
quency only (À589 and À728 cmÀ1 respectively) and
show the hydrogen moving across the Li–Li bond and
the lithium atoms. Their structural data are available
from Table 5, while the calculated structures are pre-
sented in Fig. 3.
O
O
Li Li
O
Li Li O
O
Pathway 4
Pathway 1
Li Li
O
+
Pathway 2
Pathway 3
Li
Li
O
Li
O
O
Li O
Scheme 7. Formation of most stable first intermediate when a second anisole molecule is considered.

1516
O. Mendoza et al. / Journal of Organometallic Chemistry 690 (2005) 1511–1522
E
O
2Li
+
2
O
O
TS
+
Li
+ Li
2
Li
Li
O
1a
O
Li
Li
O
O
4a
+
O
Li Li
1b
O
Li Li O
4b
reaction coordinates
Scheme 8. Possible reaction steps for pathway 1 before reaching the transition state.
The p-coordination after the activation is only stable
proaches C1 and does not coordinate with any other
carbon. Structural data are presented in Table 9.
on pathway 2 (7), as Scheme 9 shows. For pathway 1 a
second intermediate with a p-interaction is not found
(see Tables 6 and 7).
3.3. Pathway 4
The last step before the formation of 2-lithio anisole
and lithium hydride, involves a final intermediate. As in
one anisole pathway, the anisole lithium p-interaction
disappears and a C–Li bond is found instead.
The last pathway studied conferred a special case.
The intermediate with lowest energy 12b show the sec-
ond anisole p-bonded with Li(2) where, as in path 3,
two C–Li bonds characterise this coordination.
The configuration of 12a is characterised by the posi-
tion of the electron pair that is transferred from Li2 to
the aromatic ring during the C–H activation. A notably
different structure can be observed when the electrons
are still paired (singlet configuration) or when one elec-
tron from the Li–Li bond has been moved already
(triplet).
The singlet configuration presents an expected anisole
molecule double bounded with a dilithium species, while
the second anisole has two C–Li bonds with Li(2)
(Scheme 11). However this is not the stable
configuration.
The calculated triplet structure has a negligibly lower
energy of À0.5 kcal/mol, in which the two lithium atoms
do not appear to be bonded (Li–Li: 395.1 pm) and the
second anisole shows a clear p-interaction.
The TS (Table 5) for the C–H activation step also
shows a singlet structure. The Li(2)–H does not appear
bonded (278.6 pm) and the second anisole molecule
shows a p-interaction (Fig. 6). The frequency calculation
shows one negative vibration at À429 cmÀ1 where the
hydrogen approach to the Li(1). While previously C–H
bonds were elongated on pathway 4 the C–H bond is
bent in order to cross the Li–Li bond.
3.2. Pathway 3
When the second anisole involved has an p-interac-
tion with 1a, two new possibilities have been studied
(pathways 3 and 4).
On pathway 3, as illustrated in Scheme 10, the p-
interaction involves the lithium, which is already bonded
to the oxygen, and the aromatic ring from the second
anisole. However, the new p-system formed involves
only one aromatic carbon (C1) instead of a total coordi-
nation with the six atoms ring (Fig. 4). These C–Li
bonds are kept in all intermediates and the TS (Table
8). The numbering scheme and bonding details are
shown in Fig. 4.
The route followed by the anisole molecules is similar
than it was found on the two paths previously reported.
The first intermediate is formed by the moiety 1a and the
second bonded anisole, followed by a transition state, in
which frequency calculation shows the hydrogen moving
through the Li–Li bond (Fig. 5). The intermediate 9a
can be formed via 1b as described previously on path-
ways (Scheme 10).
As on pathway 2, a second intermediate (10) is found
after the transition state, where the p-interaction involv-
ing the whole ring and Li2 is still seen. This is followed
by the last stable intermediate (11), in which Li2 ap-
As Scheme 10 shows, the final intermediate before the
product is found on a stable single state. In 13 the

O. Mendoza et al. / Journal of Organometallic Chemistry 690 (2005) 1511–1522
1517
O
+
O
Li Li
-9.1 kcal/mol
-6.1 kcal/mol
1b
+11.2 kcal/mol
O
Li
Li
O
O
O
Li Li
O
6b
+
Li
4b
+8.6 kcal/mol
+5.4 kcal/mol
Li
3
O
Li
1a
-12.3 kcal/mol
O
O
Li
Li
-11.7 kcal/mol
6a
O
Li
O
-29.8 kcal/mol
4a
ol
TS 2
+6.0 kcal/mol
TS 1
+8.6 kcal/mol
Li
H
Li
O
O
7
-5.3 kcal/mol
-38.0 kcal/mol
Li
H
Li
O
O
O
Li
H
8
Li
O
5
-19.3 kcal/mol
-16.6 kcal/mol
O
1/4 Li4 (C6H4OMe)4 + LiH(s)
+
Scheme 9. Summary of the reactions pathways 1 and 2, when two anisole molecules are considered.
second anisole appears mainly bonded with three car-
bons in para and meta position with respect to the meth-
oxy substituent (Table 10).
All the pathways converge in the final product. In the
last step, lithium hydride and 2-lithio anisole are formed
and the second anisole is liberated (see Table 11).
4. Discussion
The theoretical study of the cocondensation reac-
tion of anisole and lithium atoms without the pres-
ence of further solvent molecules reveals four
possible pathways. All these reaction pathways lead

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O. Mendoza et al. / Journal of Organometallic Chemistry 690 (2005) 1511–1522
Table 5
Selected bond distances and negative frequencies for transition states
on pathways 1–4
activation step. This C–H activation step needs to cross
through a transition state structure, which involves
9.9 kcal/mol to activate 1a.
TS1 (pm)
TS2 (pm)
TS3 (pm)
TS4 (pm)
When the second anisole is considered, four different
pathways are found. The first intermediate that can be
considered occurs when the structure anisole–Li–Li
(1a) coordinates with a second anisole molecule and lead
4a, 6a, 9a and 12a. As Fig. 7 shows, there is a moiety
common in all the intermediates -a-, which is character-
ised by the dilithium molecule double bonded by r- and
p-coordination with the oxygen and the aromatic ring.
This moiety (1a) was identified before on the pathway
involving one anisole molecule. For all the cases, the
formation of this intermediate can be considered via
r-complex -b-. All the first intermediates involve exo-
thermic reactions.
C(1)–Li(2)
C(2)–Li(2)
C(3)–Li(2)
C(4)–Li(2)
C(5)–Li(2)
C(6)–Li(2)
228.0
218.7
217.7
226.3
249.5
249.3
À582.3
219.6
217.7
217.0
222.3
244.5
243.5
À727.9
218.8
218.0
218.1
223.0
242.2
240.0
À794.6
238.4
231.4
226.7
224.7
236.6
239.5
À429.0
m (cmÀ1
)
The formation of 4, 6, 9 and 12a, as a direct forma-
tion or via -b- intermediates, is necessary on all the cases
due to -a- structures are the closest stable systems to the
TS found. The formation of 4, 6, 9 and 12a via -b- inter-
mediates leads r-complexes with better stability and
high exothermic steps, however involves an endothermic
step between b and a structures in all the cases. These b-
intermediates were optimised as local minima, however
the reaction pathway is not an equilibrium reaction
and the b-intermediates have an additional energy due
to the high exothermic first step (formation of dili-
thium). This could supply the formation of a-intermedi-
ates via b-intermediates.
Fig. 3. Gaussview plot of the transition state structures for pathways
1–2.
Table 6
Selected interatomic distances for 4a, 5 and TS1 calculated structures
on pathway 1
During the reaction the Li2 molecule will transfer two
electrons to the aromatic ring. This electron movement
can be found already on the structures immediately be-
fore the transition state. On these structures the elec-
tronic positions are not clearly distributed. A small
energy barrier between singlet and triplet calculations
shows that the electron pair is partially transferred.
While pathway 1 shows less molecular energy on a sin-
glet calculation, there is an opposite stability on path-
ways 2–4.
4a (pm)
TS1 (pm)
5 (pm)
C(1)–H
Li–Li
108.6
292.3
202.1
231.4
229.3
138.9
363.7
197.5
193.8
228.0
321.5
232.6
190.7
223.4
216.3
O–Li(1)
Li(1)–C
Li(2)–C
Immediately after the formation of intermediates 4, 6,
9 and 12a, the C–H activation is observed. In pathways
1–3 the TS observed on this step show a similar behav-
iour: only one negative frequency where the hydrogen is
moving across the Li–Li bond while Li–Li distance is
elongated.
However in pathway 4, there is no interaction be-
tween the hydrogen and Li(2), and the negative fre-
quency shows the hydrogen bending and approaching
to Li(1).
Table 7
Selected interatomic distances for 6a, 7, 8 and TS2 on pathway 2
6a (pm)
TS2 (pm)
7 (pm)
8 (pm)
C(1)–H
Li(1)–Li(2)
O–Li(1)
108.9
281.4
206.5
229.9
248.0
142.4
359.7
200.7
197.6
219.6
301.2
264.9
220.3
211.4
228.4
323.8
253.2
197.9
239.6
209.0
Li(1)–C(1)
Li(2)–C(1)
from lithium atoms and anisole molecules to the
products 2-lithio anisole and lithium hydride via sev-
eral intermediates.
In the case of one anisole, there is a clear pathway
reaction through three intermediates. The formation
energies show that all the steps can be exothermic except
the formation of the transition state during the C–H
The relative energies of a number of different reaction
pathways can be compared. Scheme 12 shows relative
energies for the most plausible reaction pathways stud-
ied leading to the final product. For each intermediate
step on a given reaction pathway only the most stable
isomer was chosen where a number of similar isomers
were found.

O. Mendoza et al. / Journal of Organometallic Chemistry 690 (2005) 1511–1522
1519
O
+
-4.4 kcal/mol
O
Li Li
-3.2 kcal/mol
1b
Li
Li
O
O
O
Li Li
O
9b
+11.2 kcal/mol
O
12b
+7.0 kcal/mol
+6.0 kcal/mol
O
+
Li
3
O
Li
3
Li
Li
O
Li
-8.6 kcal/mol
O
-8.5 kcal/mol
1a
9a
12a
O
Li
-27.9 kcal/mol
TS 3
+5.9 kcal/mol
TS 4
+14.4 kcal/mol
Li
H
O
Li
O
10
-4.6 kcal/mol
-35.8 kcal/mol
O
Li
H
Li
Li
O
H
Li
11
O
13
O
-21.9 kcal/mol
-25.4 kcal/mol
O
1/4 Li4 (C6H4OMe)4 + LiH(s)+
Scheme 10. Summary of the reactions pathways 1 and 2, when two anisole molecules are considered.
3
5
2
2
Table 8
Selected interatomic distances for 9a, TS3, 10 and 11 on pathway 3
Li
4
1
9a (pm)
TS3 (pm)
10 (pm)
11 (pm)
1
Li
6
O
7
O
C(7)–Li(1)
C(8)–Li(1)
C(9)–Li(1)
C(10)–Li(1)
C(11)–Li(1)
C(12)–Li(1)
238.2
240.6
293.4
337.5
338.4
293.3
241.1
241.0
283.2
320.4
321.8
284.7
245.3
264.9
329.4
369.5
356.4
297.9
250.2
275.4
338.5
372.5
355.0
296.8
12
8
11
9
10
Fig. 4. Schematic structure of intermediate 9a.

1520
O. Mendoza et al. / Journal of Organometallic Chemistry 690 (2005) 1511–1522
Table 10
Selected interatomic distances for 112a, 312a, 13 and TS4 calculated
structures on pathway 4
112a
312a
TS4
13
C(7)–Li(2)
C(8)–Li(2)
C(9)–Li(2)
C(10)–Li(2)
C(11)–Li(2)
C(12)–Li(2)
233.3
238.5
302.6
349.4
344.0
292.0
240.9
238.8
240.0
241.1
244.2
246.3
239.2
245.2
249.4
245.0
236.2
236.9
305.1
270.0
249.8
267.5
303.5
321.3
Table 11
Selected interatomic distances for 312a, 13 and TS4 calculated
structures on pathway 4
312a (pm)
TS4 (pm)
13 (pm)
Fig. 5. Gaussview plot of the transition state structure on pathway 3.
C(1)–H
Li–Li
108.4
395.1
194.1
311.7
236.0
112.5
390.7
190.2
231.9
238.4
321.0
233.6
191.0
222.6
219.4
O–Li(1)
Li(1)–C
Li(2)–C
Table 9
Selected interatomic distances for 9a, 10, 11 and TS3 calculated
structures on pathway 3
9a (pm)
TS3 (pm)
10 (pm)
11 (pm)
O
Pathway 4
C(1)–H
Li(1)–Li(2)
O–Li(1)
109.0
285.9
202.5
229.1
245.1
144.2
359.0
201.6
198.3
218.8
298.7
267.1
210.7
211.4
226.0
323.7
236.3
194.9
244.0
208.3
Pathway 1
Pathway 2
O
Li(1)–C(1)
Li(2)–C(1)
Li
Li
O
O
O
O
3
1
O
Pathway 3
Li
Fig. 7. General scheme of the interaction between moiety 1a and the
second anisole occurring on all studied pathways.
Li
Li
O
Li
O
The reaction pathway involving a single anisole only
is the least stable. For this pathway all reaction interme-
diates including the TS are higher in energy than the cor-
responding step on any pathway involving two anisole
molecules.
Scheme 11. Calculated structures for 12a in singlet and triplet states.
When the second anisole molecule is considered and
it is found to have a r-coordination with the moiety
1a or 1b on pathways 1 and 2, the reaction takes place
through more stable intermediates and transition states.
Pathways 3 and 4 with p-interactions show higher ener-
getic structures in all the cases. However, pathways 1
and 2 show very similar energies for all the steps, which
are only separated by less than 3 kcal/mol.
When the intermediate activation energies are consid-
ered, that is the energy to reach the TS from a prior
intermediate (4a, 6a, 9a and 12a), pathways 1–3 require
similar activation energy of 8.6, 6.0 and 5.9 kcal/mol,
respectively. However, a significantly higher activation
energy of 14.4 kcal/mol is found on pathway 4.
Fig. 6. Gaussview plot of the transition state structure on pathway 4.

O. Mendoza et al. / Journal of Organometallic Chemistry 690 (2005) 1511–1522
1521
atmosphere of argon. All solvents were then degassed
by three freeze–pump–thaw cycles. Celite was stored in
an oven at 120 °C overnight and was dried under oil
pump vacuum for 3 h before use. For each filtration a
plug of approximately 6 cm of celite was used and each
filtration was performed under the vigorous exclusion of
1
air and moisture. H and 13C NMR spectra were ob-
tained using either a Varian 300 MHz or a Varian
500 MHz NMR machine. All chemical shifts are re-
ported in ppm and are reference to TMS. All GC MS
samples were run as liquid samples in ethylacetate using
a Finnigan Trace GC MS, equipped with a RTX-5MS
15 m column.
Scheme 12. Thermodynamical evolution for all studied pathways.
5. Conclusions
6.2. A typical cocondensation experiment
The cocondensation reaction of lithium atoms and
anisole in the presence of THF leads to an ortho CH
activation and the formation of lithium hydride. How-
ever this is not the only position that can be activated
in anisole compounds. When methyl groups are placed
in the ortho positions a C–H activation in the para posi-
tion is found as well.
Lithium atoms and anisole in the absence of a sol-
vent react under cocondensation conditions. A theo-
retical study of four possible reaction pathways
reveals some common steps. The formation of a lith-
ium–lithium bond, the interaction of this species with
the anisole molecule and the formation of a transition
state, in which the hydrogen is crossing the dilithium
species, are the main steps in all the four reaction
pathways.
The activation energy required for the CH activation
in cocondensation reactions is clearly lower than that re-
quired by other techniques. The existence of low energy
transition states in these systems is supported by theo-
retical studies of a simple system formed by one anisole
molecule and two lithium atoms. When a second anisole
is considered, while the reaction paths accessible to the
system are more complex, the energies found are lower
in all the cases. The presence of a second anisole stabi-
lises the intermediate structures and results in reactions
with a more accessible reaction path by lowering the
activation energy in the critical step.
0.53 g (0.076 mol) of lithium metal was vapourised
from an alumina crucible protected by a stainless-steel
inlet at around 800 °C over 90 min and cocondensed
with a mixture of 15 ml of the aromatic compound
and 80 ml (1.12 mol) of THF. The solution was filtered
over celite in order to remove the solid lithium hydride
by-product and unreacted lithium metal. After removal
of the solvent mixture in vacuo, a solid was isolated and
washed with 20 ml of THF. The lithiated aromatic com-
pound was identified by derivatisation with Me3SiCl.
6.3. A typical derivatisation of the lithiated aromatic with
Me3SiCl
To a room temperature solution of 0.25 g of the lith-
iated aromatic in 20 ml of THF, Me3SiCl was added
dropwise with vigorous stirring. The reaction was
judged finished when a colour-change from dark red–
yellow to pale yellow occurred. To this solution, 10 ml
of water was added and the organic phase separated
and the aqueous phase washed three times by 10 ml of
dichloromethane. The combined organic extracts were
dried over MgSO4 and then the solvent was removed un-
der reduced pressure, affording the derivative. GC MS,
1H and 13C NMR spectra were used to identify the
products.
6.4. Theoretical methods used in this study
DFT calculations were performed using B3LYP and
the 6-31G** basis set for C, H, O and Li. For this pur-
pose the program GAUSSIAN-98 was used on a Dell
workstation running Red Hat Linux. Harmonic vibra-
tional frequencies, calculated at the same level, charac-
terised stationary points and gave the zero-point
energy. The difference in the sum of the electronic and
the zero-point energies were interpreted as reaction
enthalpies at 0 K. Charge distributions were obtained
from geometry optimised structures using B3LYP/6-
31G**.
6. Experimental section
6.1. General
All experimental procedures were performed using
standard Schlenk techniques under an atmosphere of
dry argon. THF was dried and distilled from sodium
benzophenone ketyl under an atmosphere of argon.
Anisole, 2-methyl anisole and 2,4-dimethyl anisole were
dried and distilled from calcium dihydride under an

1522
O. Mendoza et al. / Journal of Organometallic Chemistry 690 (2005) 1511–1522
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[7] J.P. Dunne, M. Bockmeyer, M. Tacke, Eur. J. Inorg. Chem.
(2003) 458.
[8] M. Taddei, A. Ricci, Synthesis (1986) 633.
The general procedure applied to 2-methyl anisole
gave 6-lithio-2-methyl anisole (yellow solid) in 65%
yield, which was identified as its TMS derivative: 1H
NMR (CDCl3) d = 0.44 ppm (s), d = 2.35 ppm (s),
d = 3.78 ppm (s), d = 7.05 ppm (d, J = 7.32), d = 7.22
ppm (d, J = 7.32), d = 7.28 ppm (d, J = 7.32); 13C
NMR (CDCl3) d = 1.4, 16.8, 56.4, 121.7, 125.3, 126.5,
131.1, 134.7, 165.5 ppm.
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6.6. 2,6-Dimethyl-4-trimethylsilyl anisole
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Robb, J.R. Cheeseman, V.G. Zakrzewski, J.A. Montgomery Jr.,
R.E. Stratmann, J.C. Burant, S. Dapprich, J.M. Millam, A.D.
Daniels, K.N. Kudin, M.C. Strain, O. Farkas, J. Tomasi, V.
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Adamo, S. Clifford, J. Ochterski, G.A. Petersson, P.Y. Ayala, Q.
Cui, K. Morokuma, D.K. Malick, A.D. Rabuck, K. Raghava-
chari, J.B. Foresman, J. Cioslowski, J.V. Ortiz, A.G. Baboul,
B.B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi,
R. Gomperts, R.L. Martin, D.J. Fox, T. Keith, M.A. Al-Laham,
C.Y. Peng, A. Nanayakkara, C. Gonzalez, M. Challacombe,
P.M.W. Gill, B. Johnson, W. Chen, M.W. Wong, J.L. Andres, C.
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The general procedure applied to 2-methyl anisole
gave 4-lithio-2,6-dimethyl anisole (yellow solid) in 58%
yield, which was identified as its TMS derivative: 1H
NMR (CDCl3) d = 0.32 ppm (s), d = 2.27 ppm (s),
d = 3.71 ppm (s), d = 7.02 ppm (s); 13C NMR (CDCl3)
d = 2.3, 15.1, 58.6, 122.6, 126.2, 126.8, 156.0 ppm.
Appendix A. Supplementary data
Supplementary data associated with this article can
be found, in the online version at doi:10.1016/
j.jorganchem.2004.12.016.
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