Ring lithiation of 1,8-bis(dimethylamino)naphthalene: Another side of the 'proton sponge coin'

Article abstract of DOI:10.1039/c5dt02482j

It has been found that 1,8-bis(dimethylamino)naphthalene (DMAN), unlike N,N-dimethylaniline, undergoes ring metallation in the n-BuLi-TMEDA-Et₂O system with a low selectivity and in poor total yields. The situation is significantly improved in the t-BuLi-TMEDA-n-hexane system when 3- and 4-lithium derivatives become the only reaction products obtained in good yields. The formation of 3-Li-DMAN is especially desired since no method of direct meta-functionalization of DMAN is known to date. The relative stability and structure of DMAN lithium derivatives have been examined with the help of X-ray and multinuclear NMR measurements as well as DFT calculations.

Full text of DOI:10.1039/c5dt02482j

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DOI: 10.1039/C5DT02482J.
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Ring lithiation of 1,8-bis(dimethylamino)naphthalene: another
side of the ‘proton sponge coin’
Alexander S. Antonov,a Alexander F. Pozharskii,a,* Valery A. Ozeryanskii,a Aleksander Filarowski,b
Kyrill Yu. Suponitsky,c Peter M. Tolstoy,d and Mikhail A. Vovkd
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
It has been found that 1,8-bis(dimethylamino)naphthalene (DMAN), unlike N,N-dimethylaniline, undergoes ring
metallation in n-BuLi–TMEDA–Et2O system with low selectivity and in poor total yield. The situation is significantly
improved in t-BuLi–TMEDA–n-hexane system when 3- and 4-lithium derivatives become the only reaction products in good
yield. The formation of 3-Li-DMAN is especially fortunate since no method of direct meta-functionalization of DMAN has
been known to date. The relative stability and structure of DMAN lithium derivatives have been examined with the help of
X-ray and multinuclear NMR measurements as well as DFT calculations.
www.rsc.org/
DMANs and therefore to a great variety of other ortho-
derivatives of DMAN.2,6,7 In order to further simplify the
synthesis of ortho-substituted proton sponges and, in
Introduction
For quite a long time, ortho-substituted derivatives of 1,8-
bis(dimethylamino)naphthalene (proton sponge or briefly
DMAN) attract great interest (see ref.1 for reviews). Primarily,
this originated from a notion that an existence of the so-called
'buttressing effect' in such compounds might strongly increase
their basicity due to an extra repulsion of the peri-NMe2
particular, to avoid the halogenation step, in the present work
we investigated the direct lithiation of DMAN. We were
counting on successful results obtained earlier for lithiation of
N,N-dimethylaniline (DMA). Thus, it was shown that on
treatment of DMA with n-butyllithium in Et2O or hexane
independently on temperature only C(2)–H and C(3)–H bonds
were lithiated in a ~7:2 ratio.10 However, other authors had
later demonstrated that the selectivity of this process can be
sharply increased in the presence of N,N,N’,N’-
tetramethylethylenediamine (TMEDA) when 2-lithium-N,N-
dimethylaniline became the only reaction product in good
yield (Scheme 1).11 We hoped that under similar conditions
DMAN will behave the same way.
groups as they become closer to each other.2 In several
3,4
instances (e.g., compounds
2
and
3)
this idea really paid off
well, but in many others, e.g.
4
, failed.5 Nevertheless, the
interest to such compounds remains stable due to some other
theoretical6 and even applied7 reasons.
Traditionally, ortho-substituted derivatives of DMAN were
synthesized by multistep procedures from the appropriate
naphthalene derivatives (see e.g. ref.8). However, during the
past decade, the situation was considerably improved because
a highly selective method of DMAN ortho-bromination was
elaborated.7,9 This had opened a way to easy preparation (via
halogen-lithium exchange) of 2-lithium and 2,7-dilithium-
Scheme 1 DMA lithiation with n-BuLi
DMAN lithiation
a.Department of Organic Chemistry, Southern Federal University, Zorge str. 7,
344090 Rostov-on-Don, Russian Federation
We have conducted a large series of experiments, in which
1,8-bis(dimethylamino)naphthalene was subjected to the
action of n-butyllithium or tert-butyllithium either with or
without TMEDA at varying solvents and temperatures (Tables
1–3, Scheme 2). To establish the ratio of thus formed lithium
derivatives 5a–d, the crude reaction mixture was usually
quenched with N,N-dimethylformamide (DMF) to give easily
b.Faculty of Chemistry, University of Wroclaw, F. Joliot-Curie 14, 50-383 Wroclaw,
Poland, and Frank Laboratory of Neutron Physics, JINR, 141980 Dubna, Russian
Federation
c.. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of
Sciences, Vavilov str. 28, 119991 Moscow, Russian Federation
d.Department of Chemistry, St. Petersburg State University, Universitetskii pr. 26,
198504 St. Petersburg, Russian Federation
† Electronic supplementary informaꢀon (ESI) available: CIF file and a table giving
crystallographic data for complex (5a·Et2O)2; some computational details; a text file
of all computed molecule Cartesian coordinates in .xyz format for convenient
identified proton sponge aldehydes 6a–d
.
visualization; 1H and 13C NMR spectra for compounds 6b
for compound 5a. DOI: 10.1039/C5DT02482J
, 8 and 9. CCDC 1023357
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First of all, it was found that unlike DMA, the metallation of evidence of the high basicity of lithium derivatives 5a–d, we
DMAN is much less selective. Usually in the 1H NMR spectra of obtained one of them (5a) independently by treating ortho-
the crude reaction mixture (after addition of DMF), four bromide
7 with n-BuLi in Et2O both with and without TMEDA
'aldehyde' peaks were clearly distinguished at = 10.24, 10.03, (Table 2). The halogen-metal exchange easily occurs already at
δ
10.05 and 9.90 ppm (Figure 1). By comparison with the 1H –20 oC in the absence of TMEDA (Table 2, run 1). However, the
NMR spectra of the pure authentic aldehydes they were 2-lithium derivative has a relatively short lifetime due to its
assigned to 2-, 3- and 4-monoaldehydes 6a–c and 4,5- protolysis and accompanying Wurtz-Fittig conversion into 2-n-
dialdehyde 6d, respectively. Previously unknown 3-aldehyde butyl-1,8-bis(dimethylamino)naphthalene (8) (Table 2, runs 2
6b was isolated in the individual state and characterized by a and 3).16 Both these side reactions are strongly accelerated at
standard set of spectral measurements (see Experimental increasing temperature and adding TMEDA (runs 4, 5). In fact,
part). The detection in the final reaction mixtures of compound 5a is completely destroyed in Et2O in the presence
appreciable quantity of dialdehyde 6d, at first sight, looks of TMEDA after storage at 20–25 oC for 24 h.
unexpected. However, this is consistent with the fact of highly
selective lithiation of 1-lithiumnaphthalene to give 1,8-
dilithiumnaphthalene and is suggested to be caused by the so-
called agostic interactions.12
Fig. 1 The aldehyde groups region in the 1H NMR spectrum
(CDCl3) of the reaction mixture after its quenching with DMF
(Table 1, run 3).
Next, the replacement of diethyl ether as a solvent for
metallation of DMAN by less acidic hexane led to a substantial
increase (up to 71%) of the C-lithium derivatives total yield
(Table 3), although about 30% of the unchanged DMAN still
remained in the reaction mixture after 200 h. Since metallation
in hexane occurs only in the presence of TMEDA, one can
assume that just TMEDA is responsible for the partial
protolysis of the DMAN lithium derivatives. The relatively
modest degree of the protolysis in this case can be explained
by weaker CH acidity of TMEDA as compared with Et2O.14a
Finally, one of the most important findings made by us is that
the product ratio at metallation of DMAN in hexane is rather
dramatically changed depending on the incubation time. Thus,
in the first measurement made after 72 h, all four aldehydes
6a–d were detected in the reaction mixture with 10, 18, 6 and
8% yield, respectively (Table 3, run 1). However, with
increasing the incubation time the percentage of 2-aldehyde
and 4,5-dialdehyde was gradually decreased and after 220 h
the reaction mixture (quenched with DMF) contained only 3-
and 4-monoaldehydes in 44 and 27% yield, respectively (runs 7
and 8). This clearly indicates on the existence of kinetic and
thermodynamic control in the metallation of DMAN in the
hexane–TMEDA mixture.
Scheme 2 DMAN interaction with n-BuLi
The second point to be discussed is that the metallation of
DMAN practically does not occur in neat Et2O (Table 1, run 1)13
and slowly starts only on addition of TMEDA (runs 2 and 4).
This can be explained by a combination of two factors: 1)
pronounced tendency of n-BuLi to aggregation14 and 2) a
weakened CH-acidity of DMAN caused by the strong +M-effect
of the peri-NMe2 groups.15 Room temperature (20–25 oC) is
optimal for metallation; there are no signs of reaction at –20
oC (run 7), while heating or increasing the reaction time
decrease the total yield of the metallation products up to
100% recovery of DMAN (runs 5, 6). The increasing amount of
n-BuLi and TMEDA enhances the total yield to 37%, leaving the
products ratio almost the same (run 3). Thirdly, the total yield
of metallation products is rather modest and
a large
percentage of DMAN is usually recovered. In the control
experiments, we have established that this stems from the
expectedly high basicity of the lithium derivatives of DMAN, in
particular 5a. As a result, the lithium compounds are subjected
to protolysis by diethyl ether (or Et3N in run 8) thus being
converted into initial diamine
1. To gain more convincing
2 | Dalton Trans., 2015, 00, 1-3
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Table 1 Influence of the reaction conditions on DMAN lithiation with n-BuLi
Compounds detected in the final reaction mixture, %
n-BuLi,
eq.
TMEDA,
eq.
Run
Solvent
Time, h
Т, oC
1
6a
6b
6c
6d
∑6a–d
1
2
3
4
5
6
7
8
9
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et3N
Hexane
1
1
4
1
1
1
1
1
1
0
1
4
1
1
1
1
1
1
24
24
24
6
122
24
24
24
24
25
25
25
25
25
35
–20
25
25
100
92
63
0
2
10
1
0
0
0
0
6
0
3
15
2
0
0
0
0
10
0
3
10
1
0
0
0
0
3
0
<1
2
<1
0
0
0
0
5
0
8
37
4
0
0
0
0
24
96
100
100
100
100
76
destabilization may be caused by a generally high π-excessity of the
Apparently, in the beginning due to the combined action of the
DOM effect (directed ortho-metallation)17 and the above DMAN molecule,1b which might greatly increase due to appearance
mentioned agostic interactions, the appreciable amounts of 2-
lithium- 5a and 4,5-dilithium 5d derivatives are formed along
with 5b and 5c. However, gradually the first two compounds
undergo transformation into their more stable counterparts 5b
and 5c, of which 5b is clearly more stable. The relative
instability of 5a and 5d may result from several reasons.
of the additional pair of the anionic centres. One cannot also
disregard the strong deformation of the naphthalene ring in 5d
caused by coordination of each lithium atom with both peri-
positions (see below).
We then found that the metallation of DMAN with tert-butyllithium
in hexane in the presence of TMEDA occurs considerably faster and
under milder conditions as compared with n-BuLi. This is in
accordance with the higher nucleophilicity of the tert-butyl anion.14a
However, the most remarkable fact is that no 2-lithium and 4,5-
dilithium derivatives are formed at all when using t-BuLi (Table 4,
Figure 2). Evidently, the greater bulkiness of this reagent directs the
DMAN metallation into the sterically more available 3 and 4
positions thus preventing the second peri-metallation.
Table 2 Experiments showing instability of 5a in Et2O
Products,a %
Run
TMEDA, eq.
Т, oC
Time, h
1
6a
8
1
2
3
4
5
0
0
0
0
1
–20
–20
–20
25
0.05
0.3
24
24
24
5
95
0
0
6
30
54
16 84
16 78
26 44
46 <1
25
aAfter treating the reaction mixture with DMF
Table 3 Dependence of DMAN lithiation in hexane on
incubation time (4 eq. n-BuLi, 4 eq. TMEDA, 25 oC)
Products,a %
Run
Time, h
1
6a
10
9
6b
18
21
23
25
30
39
42
44
6c
6
9
12
13
20
22
25
27
6d
8
6
6
6
6
3
2
0
∑6a–d
42
45
47
52
60
64
69
71
1
2
3
4
5
6
7
8
72
96
58
55
53
48
40
34
31
29
120
144
168
192
216
264
6
8
4
2
Fig. 2 The aldehyde groups region in the 1H NMR spectrum
(CDCl3) of the reaction mixture in hexane after its quenching
with DMF (Table 4, run 4).
0
0
aAfter treating the reaction mixture with DMF
We consider the formation of 3-lithium derivative 5b an
especially remarkable circumstance. The matter is that it
opens the route to the synthesis of almost unknown 3-
substituted derivatives of DMAN, which cannot be obtained,
for example, in the reactions of DMAN with electrophiles and
other reagents.1b Along with this, we obtained in quite
Thus, in molecule 5а, the repulsion of three juxtaposed lone
electron pairs might be rather severe, in contrast to the parent
DMAN and isomeric 5b and 5c where only two electron pairs are
involved in the repulsion. As for dilithium derivative 5d, its
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appreciable yield (in addition to meta-aldehyde 6b
) 3- typical proton sponge pattern in the aromatic region and low
methylthio- 9 and 4-methylthio 10 derivatives of DMAN by temperature sensitivity. The only exception is a doublet at δ =
treatment the mixture of 5b and 5c with dimethyldisulfide 7.65 ppm, whose considerable low-field shift as well as a
1
(Scheme 3).
resemblance with the similar peak in the H NMR spectrum of
phenyllithium22 allow to assign it to the H-3 proton deshielded
Table 4 DMAN lithiation with 4 eq. tert-BuLi in hexane
by the neighbouring C–Li bond. The high-field signal at δ = 6.51
Products,a %
ppm on the basis of common regularities of 1H NMR spectra of
proton sponges1b can be assigned to the Н-7 hydrogen. As
expected, the carbanionic nature of 2-Li-DMAN causes
noticeable shielding of other H-atoms including those of NMe2
groups. Perhaps, an appearance of the latter is especially
informative from the structural point of view (Figure 4). At –5
oC (the highest temperature employed) the NMe2 groups
Run
TMEDA, eq.
Time, h T, oC
1
6b
0
22
32
38
6c
0
26
32
38
1
2
3
4
0
4
4
4
24
24
24
96
25
–20
25
100
52
35
24
–20
a After treating the reaction mixture with DMF
display two close peaks at
δ 2.7 ppm. Normally, such chemical
shift is typical for the proton sponge NMe2 groups whose
methyls are turned outward and axes of electron pairs are
directed inward of the internitrogen space (in,in
conformation).21,23
Scheme 3 DMAN Interaction with t-BuLi
Structural studies
X-ray measurements. During the preparation of 2-lithium
derivative of DMAN from bromide via halogen-lithium
7
exchange we have noticed that 5a is precipitated from the
ether solution as yellow crystals in the form of thin plates. This
allowed us to carry out their X-ray study. It was established
that compound 5a, like other lithiumnaphthalenes,18,19 exists
in the solid as a nearly symmetric dimer with the four-
coordinated lithium atoms (Figure 3). Along with the C(2) and
C(2’) atoms of the two aromatic rings, the lithium atoms form
a rhombic structure with the following parameters:
[67.1(3)o], C–Li–C [112.9(3)o], C–Li (2.20/2.22 Å). Two other
∠Li–C–Li
Fig. 3 Molecular structure of (5a·Et2O)2
∠
ligands for each lithium atom are the molecule of diethyl ether
and the out-inverted 1-NMe2 group with the O…Li and N…Li
distances equal to 1.952(8) and 2.111(8) Å, respectively.20 The
angle between the average naphthalene ring plane and the
rhombus plane (C–Li)2 is 64.4(2)o.
However, on cooling the signals of two NMe2 groups are
gradually separated due to moving one of them into the high
field region. This pattern is usually the case when 8-NMe2
group is additionally pyramidalized under pressure of its 1-
NMe2 counterpart which undergoes nitrogen inversion due to
coordination with an appropriate ortho-substituent.23,24 From
this, one can assume that at –5 oC, a fast equilibrium takes
place mostly between structures of type 11a and 11b in which
NMe2 groups retain the in,in conformation incapable to
coordination with the 2-lithium atom (Scheme 4). Probably, at
further cooling, due to a slowing down diffusion and dynamic
processes, the coordination of Li with the 1-NMe2 group
becomes energetically more probable and structures 11c and
11d with the inverted nitrogen atoms come into play. Since no
doubling of signals of aromatic protons occurs (see for
example ref.6) the coalescence temperature is not yet reached
NMR studies and solution behaviour. It seems interesting to
clarify whether the dimeric structure of 5a is also valid in
solution. With this in mind we carried out the variable
temperature 1H, 7Li and 13C{1H} NMR experiments with 5a
dissolved in non-deuterated THF (this technique is known as
No-D spectroscopy).19a,b The 1H and 13C{1H} spectra revealed
the presence in the solution of small amounts (about 10%
each) of DMAN and bromide
7 (Figures 4, 5). Fortunately, their
signals where not overlapped with these of 5a and could be
easily singled out by comparison with the spectra of the
authentic samples. Besides, the temperature lowering led to a
considerable increase of the solution viscosity that resulted in
almost complete disappearance of the admixture signals. As
seen from Figure 4, the proton spectra of 5a demonstrate a
even at –90 oC, i.e. equilibriums between forms 11a
–d still
remains rapid in the NMR time-scale. Such viewpoint is also
consistent with the lithium NMR spectra (Figure 6), which
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demonstrate shifting the 7Li signal to a higher field as the together with small impurity peaks belonging to the proton
temperature decreases. This can reflect a stronger electron sponge and 2-bromide . The broaden low-field signal at δ =
donation of the 1-NMe2 group to the Li atom as compared 172.4 ppm is the most important one. It can be unambiguously
1
7
with the oxygen atom of THF.
assigned to the carbon atom of the C–Li bond. This follows
Further information was obtained from 13C NMR spectrum of both from the absence of any likely peaks in the 13C NMR
5a registered at –90 oC (Figure 5). In the aromatic region it spectrum of DMAN1b and its similarity with that of 1-
contains ten intensive peaks of the naphthalene carbon atoms dimethylamino-8-lithiumnaphthalene (δ
=
185.5 ppm).19b
Fig. 4 Fragments of the 1H No-D temperature depending NMR spectrum of 2-Li-DMAN 5a (THF, 500 MHz). Admixture signals of
and are marked with # and *, respectively.
1
7
Fig. 5 Fragments of the 13C No-D NMR spectrum of 2-Li-DMAN 5a at –90 oC (THF, 126 MHz).
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7
C(2) and C(2') carbon atoms simultaneously with two Li nuclei
each of which has nuclear spin I = 3/2 (92.4% natural
abundance).25 Although the peak at 172.4 ppm is rather poorly
resolved, we think that its appearance taken in combination
with the above discussed NMR 1H and 7Li data also serve in
favour of the rapid equilibria between structures 11a–d
.
Apparently, at –90 oC a contribution of dimeric form 11d
considerably increases. Indirectly, this can be judged by the
peak width near the base line which is equal to 154 Hz (Figure
5). Since a value of J7Li-13C is commonly equal to 20.5 Hz19a,b the
spectral width of this signal is much better adapted for a
septet rather than a quartet signal. Thus, with a reasonable
extent of probability one can affirm that the dimeric structure
11d prevails in solution at low temperature while at the higher
temperature the equilibrium shifts to the monomeric form
11a. Some contribution of intermediate forms like 11b and 11c
should not be discounted as well.
Theoretical background. To get some more information on the
properties of DMAN lithium derivatives, we have conducted
the DFT calculations by B3LYP method with the 6-311+G(d,p)
and 6-311G(d,p) basis sets. The results obtained using both
sets are in good agreement. The calculations of the vibrations
and zero-point energies (ZPE) are also accomplished. We were
particularly interested in two issues: 1) what are the structures
of lithium compounds in the gas phase and how they change
on solvation and 2) what is the driving force for the
transformation of 2-lithium- and 4,5-dilithium-DMANs into
their 3- and 4-lithium counterparts in hexane. Regarding the
first issue, the calculations unambiguously demonstrate that in
the gas phase the structure of 2-Li-DMAN with the out-
inverted 1-NMe2 group is the most beneficial obviously due to
Scheme 4 Postulated aggregates of 2-Li-DMAN 5a in THF
solution
the formation of the N→Li coordination bond (Figure 7).
E = –660.875583 a.u.
E = –660.866515 a.u.
ꢀE = 4.31 kcal/mol
Fig. 7 Calculated geometries (selected bond lengths and distances in
Å, angles in deg) for the in,out- and in,in-conformers of 2-Li-DMAN
5a [B3LYP/6-311+G(d,p)].
Fig. 6 7Li temperature depending No-D NMR spectrum of 2-Li-
DMAN 5a (THF, 194 MHz).
In general, the difference in stability of the non-solvated
5а(in,out) and 5a(in,in) forms varies in the range of 4–6
kcal/mol (depending on the theoretical basis) in favour of the
former. A relatively small “outness” of the 1-NMe2 group in
5а(in,out) (∑N1 = 346o) is typical for proton sponges with such
A considerable high-field shift of this signal for 5a can be
attributed to the +M-effect of peri-NMe2 groups. If the dimeric
structure of 5a retains in solution, the signal at 172.4 ppm
should appear as septet19b due to the spin-spin coupling of the
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geometry.23 This is caused by the fact that translocation of Our calculations were also rather helpful in explaining the
methyls of the 1-NMe2 group into the internitrogen space transformation of 2-lithium- and 4,5-dilithium-DMANs into
meets the resistance from the 8-NMe2 group, strongly their 3- and 4-congeners in hexane. This follows from Figure 9
increasing the N…N distance (3.09 Å for 5a against ca. 2.80 Å where total energies and their differences for the optimized
for
1). Notably, that the transition to the real dimeric structure structures of the Li-DMANs are depicted. To get comparable
(
5a·Et2O)2 with the four-coordinated lithium atoms results in results, the structures chosen should contain an equal amount
decreasing of both the 1-NMe2 group “outness” (∑N1 = 350o) of the proton sponge residue, TMEDA and lithium atoms (SI-3).
and the N…N distance (3.01 Å). Simultaneously, a considerable This approach for the calculation of energy parameters is
elongation of the C–Li and N–Li bonds takes place (Table 5). grounded in the literature.27 One can see that the lithium
The tendency to elongation of the C–Li bond also appears in derivatives under consideration are clearly divided into two
the DFT calculations for dimeric 3- and 4-lithium derivatives of groups: less stable 2-lithium and 4,5-dilithium-DMANs and
DMAN on their coordination with TMEDA molecules (SI-2).
much more stable (nearly by 16 kcal/mol) 3- and 4-lithium
DMANs. The slight difference in the energies of 5c and 5b
obviously lies within the error of calculations and is in
accordance with their close proportion on metallation of
DMAN with tert-BuLi.
Table 5 Selected geometrical parameters of structure 5a(in,out)
obtained from DFT calculations
experimental X-ray study
C–Li,
[B3LYP/6-311+G(d,p)] and
N–Li,
Å
N…N,
Å
∑N1,
Deg.
Structure
5а
Method
DFT
Å
NMe2
1.934
2.051
1.992
2.141
2.129
3.093
3.090
3.092
346.1
347.3
346.7
Me2N
NMe
2 Me2N
Me2N Me2N
11с≡5a.THF2 DFT
Li
NMe2
5а·TMEDA
DFT
2.029
NMe2
NMe2
5a—TMEDA
2.198(9);
2.215(9)
Li
(5a·Et2O)2
Xꢀray
2.111(8) 3.011(5) 350.1(9)
NMe2
Li
Me2N
NMe2
Me2N Me2N
Li
NMe2
The calculated gas-phase structure of 4,5-dilithium DMAN 5d is
also rather intriguing. Both lithium atoms of 5d are located
symmetrically above and below the naphthalene ring plane
forming identical bonds with the C(4) and C(5) ring atoms
(Figure 8, see also SI-2). This result does not dependent on the
coordination saturation of the Li atoms. The only point is that
while for the ether complex 5d·(Et2O)4 both lithium atoms are
tetracoordinated (Figure 8a), we failed to find a similar global
energy minimum for the complex 5d·(TMEDA)2. The matter is
that during the optimization, one of the NMe2 groups of
TMEDA, possibly due to steric reasons, remains unbounded
with the lithium ion (Figure 8b). Anyway, the structure of
5d·(TMEDA)2 strongly reminds that of 2,2’-dilithiumbiphenyl–
(TMEDA)2 complex, which has been resolved by X-ray
experiment.26
NMe2
(5b—TMEDA)2
5a—TMEDA
E1 = –2017.531016 a.u.
E2 = – 2017.559526 a.u.
Me2N
NMe2
Me2N
NMe2
Me2N
Me2N
Me2N
Li
Li
NMe2
Li
Li
NMe2
NMe2
Me2N
N
Me2N
NMe2
Me2
—
5d (TMEDA)2
Me2N
(5c—TMEDA)2
E3 = –2017.560870 a.u.
E (kcal/mol)
NMe2
1
E4 = –2017.534842 a.u.
E1
2.4
E4
17.9
15.5
18.7
16.3
E2
0.8
E3
(a)
(b)
Fig. 8 The calculated gas-phase structures of 5d·(Et2O)4 (a) and
5d·(TMEDA)2 (b) [B3LYP/6-311+G(d,p)].
Fig. 9 Absolute (a.u.) and relative (kcal/mol) energies of Li-
DMANs complexes with TMEDA [B3LYP/6-311+G(d,p)].
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From the above one can conclude that on the whole the structures correspond to the minimum on the potential energy
stability of lithium-DMANs and therefore the ease of their surface (PES) and obtaining zero-point Energies (ZPE) values.
formation mostly results from their proton sponge specifics. Monitoring of DMAN lithiation. To investigate the influence of
There can be little doubt that the dominant factor here is a the experimental conditions on the proton sponge lithiation
sharp increase of electrostatic repulsion between the nitrogen with n-BuLi, a solution of DMAN
1 (100 mg, 0.5 mmol) was
electron pairs and additionally arising carbanionic centres. dissolved in 1 mL of the corresponding solvent (Et2O, n-
Obviously, the molecule destabilization grows as a number of hexane, or Et3N) and placed in a glass ampoule. The required
the latter and their proximity increases.
quantity of n-butyllithium (1.6 M solution) and dry TMEDA
(optionally) were added to the reaction mixture under an
argon atmosphere. The ampoule was sealed and kept under
conditions shown in Tables 1 and 3. An equimolar quantity of
dry N,N-dimethylformamide was then added to the reaction
Conclusions
In
summary,
1,8-bis(dimethylamino)naphthalene
o
mixture at –20 C. The reaction mass was kept additionally for
demonstrates rather poor ability to the ring metallation under
ordinary conditions (n-BuLi, Et2O, TMEDA) which is combined
with the low selectivity of the process. Undoubtedly, this
results from strong electron-donor effect of two NMe2 groups,
which lowers the ring CH-acidity. Figuratively speaking, the
acidic side of the “proton sponge coin” is suppressed by its
basic counterpart. Yet, using t-BuLi–TMEDA system in hexane
allows considerable improving the situation since almost equal
quantities of only 3- and 4-lithium derivatives of DMAN are
formed in this case in good total yield. For the first time this
opens synthetic perspectives for the meta-derivatization of
DMAN. As to 2- and 4-lithium derivatives as well as di-lithium
compounds of DMAN, they can be preferably prepared from
the corresponding bromides by bromo-lithium exchange. It has
also been disclosed that 2-lithium-DMAN exists in the solid and
gas phase with the out-inverted 1-NMe2 group while in
solution it likely equilibrates between several structures. The
first example of fixation of the proton sponge non-
conventional in,out conformation via the direct coordination
with the metal atom has been disclosed. Possibly our work
24 h at –20 oC and treated with water (5 mL). The products
were extracted with Et2O (2 × 5 mL) and the solvent was
evaporated to dryness. The residue (20 mg) was dissolved in
1
CDCl3 (0.7 mL) and analyzed by H NMR. The authentic DMAN
aldehydes were prepared as described in the literature.30,31
DMAN lithiation with tert-butyllithium. Dry TMEDA (5.4 mL,
9.2 mmol) and tert-butyllithium 1.7 M solution in pentane (1.3
mL, 9.2 mmol) were added by syringe to a solution of DMAN 1
o
(500 mg, 2.3 mmol) in dry n-hexane (5 mL) at –20 C under an
argon atmosphere. The resulted yellow-brown suspension I
was stirred for 96 h at –20 oC.
3-Formyl- and 4-formyl-1,8-bis(dimethylamino)naphthalenes
6b and 6с. Absolute N,N-dimethylformamide (1.1 mL, 12
mmol) was added to suspension I. The reaction mass was
o
additionally stirred for 24 h at –20 C and treated with water
(10 mL). The products were extracted with Et2O (2 × 25 mL),
the solvent was evaporated to dryness and the residue was
chromatographed on silica gel with Et2O–n-hexane 1:1 mixture
as the eluent. Yellow fractions with Rf = 0.5 (6b) and 0.2 (6c
)
were collected.
opens
a window to new and very specific kind of
3-Formyl-1,8-bis(dimethylamino)naphthalene
(6b): yellow-
organometallics whose basicity supersedes that of most
aryllithiums and even approaches the basicity level of
alkyllithiums. Indeed, the abnormally high basicity of 2-lithium
DMAN was recently applied in a new indole synthesis.28
orange oil; yield 180 mg (32%). Found: C, 74.39; H, 7.45; N,
11.53. Calc. for C15H18N2O: C, 74.35; H, 7.49; N, 11.56. UV/vis
(MeCN), λmax (lgε): 345 (3.51), 332 (3.46), 285 (3.97), 251
(4.60), 249 (4.65), 247 (4.66), 243 (4.63), 234 (4.70), 231 (4.69),
228 (4.70), 222 (4.66). IR (liquid film), ν
max/cm–1 1696 (C=O). 1H
Experimental
NMR (250 MHz, δ, CDCl3): 10.03 (1H, s), 7.79 (1H, d, J = 1.4 Hz),
7.47 (1H, dd, J = 7.9, 1.0 Hz), 7.38 (1H, t, J = 7.7 Hz), 7.30 (1H,
d, J = 1.5 Hz), 7.06 (1H, dd, J = 7.5, 1.1 Hz), 2.81 (6H, s), 2.79
(6H, s). 13C NMR (63 MHz, δ, CDCl3): 193.3, 152.2, 151.4, 137.5,
134.3, 129.4, 127.1, 123.7, 123.2, 116.2, 107.7, 44.6, 44.5. MS
(EI), m/z (I, %): 29 (47), 30 (10), 42 (51), 43 (16), 44 (37), 45
(13), 115 (12), 126 (17), 127 (35), 128 (15), 140 (10), 154 (19),
155 (10), 167 (21), 168 (32), 169 (11), 170 (12), 182 (15), 183
(10), 196 (72), 197 (20), 198 (30), 210 (40), 211 (65), 212 (33),
227 (34), 242 (M+, 100), 243 (17).
General
considerations
.
Commercially
available
tetrahydrofuran and diethyl ether were distilled over sodium
and benzophenone. Hexane was distilled over sodium. Liquid-
1
state H and 13C{1H} NMR experiments were performed at 250
MHz for H, and 63 MHz for 13C (Southern Federal University
1
facilities) and 500 MHz for H, 126 MHz for 13C, and 194 MHz
1
for 7Li (Centre for Magnetic Resonance, St. Petersburg State
University) using the solvent peaks as the internal reference.
Mass-spectra were obtained in an electron impact mode at 70
eV. X-Ray measurements were conducted with a Bruker APEX2
4-Formyl-1,8-bis(dimethylamino)naphthalene (6c): orange oil;
yield 140 mg (25%). Characterization data were consistent
with those reported in the literature.30
diffractometer (Mo-Kα line, graphite monochromator,
ω-
scans). The quantum mechanical simulations were carried out
using the Gaussian 09 suite of programs.29a The energy
minimization was performed using DFT with the B3LYP
functional.29b The 6-311+G(d,p) and 6-311G(d,p) basis sets
were applied during the simulations.29c–f Harmonic frequencies
calculations were performed to confirm that the obtained
3- and 4-(methylthio)-1,8-bis(dimethylamino)naphthalenes 9
and 10. Absolute dimethyldisulfide (1.0 mL, 10 mmol) was
added to suspension I. The reaction mass was stirred
additionally for 24 h at –20 oC and treated with water (10 mL).
The products were extracted with Et2O (2 × 25 mL), the solvent
8 | Dalton Trans., 2015, 00, 1-3
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was evaporated to dryness and the residue was refinement was carried out with the SHELXTL program.33 The
chromatographed on Al2O3 with EtOAc–n-hexane 1:20 mixture details of the data collection and crystal structure refinement
as the eluent. Yellow fractions (almost colourless on are summarized in Table SI-1 (Supporting Info). CCDC 1023357
adsorbent) with Rf = 0.6 (
9) and 0.4 (10) were collected.
contains the supplementary crystallographic data for this
3-Methylthio-1,8-bis(dimethylamino)naphthalene
(
9
): pale paper. These data can be obtained free of charge via
yellow oil with a weak “sulfide” odour; yield 192 mg (31%). www.ccdc.cam.ac.uk/data_request/cif.
Found: C, 69.23; H, 7.72; N, 10.79. Calc. for C15H20N2S: C, 69.19; 2-n-Butyl-1,8-bis(dimethylamino)naphthalene (8)
.
1.6
M
1
H, 7.74; N, 10.76. H NMR (250 MHz, δ, CDCl3): 7.20–7.30 (2H, solution of n-butyllithium (2 mL, 3.2 mmol) was added to a
m), 7.11 (1H, d, J = 1.8 Hz), 6.84 (1H, dd, J = 6.7, 2.0 Hz), 6.78 solution of bromide 7 (540 mg 1.8 mmol) under an argon
(1H, d, J = 1.8 Hz), 2.78 (6H, s), 2.76 (6H, s), 2.55 (3H, s). 13C atmosphere at room temperature. The resulted yellow
NMR (63 MHz, δ, CDCl3): 151.0, 138.3, 135.5, 126.3, 120.8, suspension was treated with n-butylbromide (5 mL, 46.6
118.6, 117.3, 112.4, 112.3, 44.4, 44.3, 15.6. MS (EI), m/z (I, %): mmol), refluxed for 2 h and quenched with water (10 mL). The
12 (24), 15 (45), 16 (12), 18 (27), 27 (13), 28 (46), 29 (26), 41 products were extracted with CH2Cl2 (2 × 5 mL). The solvent
(61), 42 (49), 43 (100), 44 (37), 45 (23), 47 (13), 55 (68), 56 was removed in vacuum and the residue was
(20), 57 (85), 58 (15), 67 (25), 69 (59), 70 (15), 71 (41), 79 (11), chromatographed on alumina with 1:1 Et2O–n-hexane mixture
81 (32), 82 (11), 83 (41), 84 (10), 85 (26), 93 (10), 95 (34), 96 as the eluent. The colourless fraction (brown in iodine vapour)
(12), 97 (35), 109 (21), 111 (25), 115 (21), 123 (13), 125 (17), with Rf = 0.3 was collected. Butylnaphthalene
8 was obtained
127 (13), 154 (15), 167 (13), 168 (24), 169 (18), 196 (12), 201 as brown oil (245 mg, 50%). Found: C, 80.00; H, 9.66; N, 10.34.
(10), 214 (36), 215 (14), 216 (23), 228 (15), 229 (34), 230 (28), Calc. for C18H26N2: C, 79.95; H, 9.69; N, 10.36. 1H NMR (250
231 (10), 245 (23), 260 (M+, 70), 261 (15).
MHz, δ, CDCl3): 7.41 (1H, d, J = 8.3 Hz), 7.37 (1H, dd, J = 8.0, 1.1
4-Methylthio-1,8-bis(dimethylamino)naphthalene (10): dark- Hz), 7.26–7.18 (2H, m), 7.03 (1H, dd, J = 7.4, 1.0 Hz), 2.94 (6H,
yellow oil with a weak “sulfide” odour; yield 198 mg (32%). s), 2.76–2.68 (8H, m), 1.64–1.50 (2H, m), 1.37 (2H, td, J = 14.3,
Characterization data were consistent with those reported in 7.1 Hz), 0.93 (3H, t, J = 7.2 Hz). MS (EI), m/z (I, %): 29 (54), 32
the literature.31
(85), 39 (19), 41 (68), 42 (44), 43 (81), 44 (27), 55 (40), 56 (20),
1,8-Bis(dimethylamino)-2-lithiumnaphthalene
(
5а). For No-D 57 (54), 58 (38), 69 (20), 70 (11), 71 (25), 77 (10), 83 (17), 85
NMR measurements, 5a was prepared as follows: a solution of (14), 97 (12), 115 (13), 127 (12), 149 (19), 154 (11), 167 (17),
2-bromo-1,8-bis(dimethylamino)naphthalene7,21
) (161 mg, 168 (31), 169 (13), 181 (16), 182 (26), 183 (11), 196 (38), 197
(7
0.55 mmol) in n-hexane (1 mL) was placed into NMR tube. n- (23), 211 (13), 224 (16), 225 (12), 226 (18), 239 (11), 240 (20),
BuLi (1.6 M solution in hexanes, 0.38 mL, 0.6 mmol) was 241 (33), 255 (27), 270 (M+, 100), 271 (21).
added to the solution via syringe under an argon atmosphere.
The solvent was removed in vacuum and the NMR tube was
Acknowledgements
cooled by liquid nitrogen. Absolute THF (0.7 mL) was distilled
direct into the NMR tube. The spectral measurements were
performed immediately. 1H NMR (500 MHz, δ, THF, –90 оС):
7.65 (1H, d, J = 5.3 Hz), 7.01 (1H, d, J = 7.5 Hz), 6.83 (1H, d, J =
6.7 Hz), 6.80 (1H, t, J = 7.1 Hz), 6.53 (1H, d, J = 6.9 Hz), 2.69
Financial support from the Russian Foundation for Basic
Research (projects 12-03-31172 and 14-03-00010) is greatly
acknowledged. We wish to thank Dr. M. E. Kletskii (Southern
Federal University) for stimulating discussion and valuable
suggestions during initial steps of the quantum-chemical
calculations.
о
(9H, s), 2.55 (7H, s). 13C NMR (126 MHz, δ, THF, –90 С): 172.4
(m), 156.3, 148.5, 139.8, 135.9, 121.4, 120.1, 117.3, 116.4,
108.5, 45.0, 44.2.
For X-ray analysis of 5a, single crystals were obtained as
follows: a solution of n-BuLi (1.6 M, 0.2 mL, 0.32 mmol) was
very slowly added to a solution of bromide 7 (100 mg, 0.34
mmol) in absolute Et2O (1 mL) at –20 oC under an argon
atmosphere. After 30 min the solution was removed via
syringe and the resulted yellow crystals were immediately
covered with 1 ml of Fomblin® Y to prevent the interaction
with air components. When a suitable single crystal sample
was chosen, it was accurately (avoiding a contact with air)
transferred into the epoxy glue and then mounted onto the
glass fibre attached to the goniometer head. X-Ray experiment
was carried out at 120 K. Collected data were analyzed by the
SAINT and SADABS programs incorporated into the APEX2
program package.32 The structure was solved by the direct
method and refined by the full-matrix least-squares procedure
against F2 in anisotropic approximation. Positions of hydrogen
atoms were calculated and included in the refinement within
isotropic approximation using the riding model. The
Notes and references
1
(a) F. Hibbert, Acc. Chem. Res., 1984, 17, 115; (b) A. F.
Pozharskii and V. A. Ozeryanskii, in The Chemistry of Anilines
ed. by Z. Rappoport, Chichester: J. Wiley and Sons, 2007,
Part 2, Chapter 17, pp. 931–1026.
2
A. F. Pozharskii, O. V. Ryabtsova, V. A. Ozeryanskii, A. V.
Degtyarev, O. N. Kazheva, G. G. Alexandrov and O. A.
Dyachenko, J. Org. Chem., 2003, 68, 10109.
3
4
5
F. Hibbert and K. P. P. Hunte, J. Chem. Soc., Perkin Trans. 2,
1983, 1895.
V. A. Ozeryanskii, A. A. Milov, V. I. Minkin and A. F.
Pozharskii, Angew. Chem., Int. Ed., 2006, 45, 1453.
A. V. Degtyarev, O. V. Ryabtsova, A. F. Pozharskii, V. A.
Ozeryanskii, Z. A. Starikova, L. Sobczyk and A. Filarowski,
Tetrahedron, 2008, 64, 6209.
6
7
A. F. Pozharskii, A. V. Degtyarev, V. A. Ozeryanskii, O. V.
Ryabtsova, Z. A. Starikova and G. S. Borodkin, J. Org. Chem.,
2010, 75, 4706.
N. J. Farrer, R. McDonald and J. S. McIndoe, Dalton Trans.,
2006, 4570.
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8
9
H. A. Staab, A. Kirsch, T. Barth, C. Krieger and F. A.
inverted NMe2 group had also been registered as a minor
admixture in the gas phase.21 This form can be stabilized via
intramolecular hydrogen bonding with an appropriate ortho-
substituent (see Ref.6 for an example), and compound 5a is
Neugebauer, Eur. J. Org. Chem., 2000, 1617.
A. F. Pozharskii and V. A. Ozeryanskii, Russ. Chem. Bull.,
1998, 47, 66.
10 A. R. Lepley, J. Org. Chem., 1966,
11 H. T. Al-Masri, J. Seizer, P. Lönnecke, S. Blaurock, K.
7
, 2047.
the first case of such stabilization caused by the N
coordination.
21 A. Szemik-Hojniak, J. M. Zwier, W. J. Buma, R. Bursi and J. H.
→metal
Domasevitch and E. Hey-Hawkins, Tetrahedron, 2004, 60
333.
,
Van der Waals, J. Am. Chem. Soc., 1998, 120, 4840.
12 (a) J. M. Saa, J. Morey, A. Frontera and P. M. Deya, J. Am. 22 T. R. Hoye, B. M. Eklov, T. D. Ryba, M. Voloshin and L. J. Yao,
Chem. Soc., 1995, 117, 1105. (b) W. Bauer, T. Clark and P. Org. Lett., 2004, , 953.
von R. Schleyer, J. Am. Chem. Soc., 1987, 109, 970. (c) A. F. 23 A. F. Pozharskii, A. V. Degtyarev, O. V. Ryabtsova, V. A.
6
Pozharskii and O. V. Ryabtsova, Russ. Chem. Rev., 2006, 75,
709. (d) E. V. Anslyn and D. A. Dougherty, Modern Physical
Ozeryanskii, M. E. Kletskii, Z. A. Starikova, L. Sobczyk and A.
Filarowski, J. Org. Chem., 2007, 72, 3006.
Organic Chemistry; University Science Books: Sausalito, CA, 24 N. J. Farrer, K. L. Vikse, R. McDonald and J. S. McIndoe, Eur. J.
2006; p 727. Inorg. Chem., 2012, 733.
13 Previously it has been shown that the proton sponge itself is 25 Theoretically, the dimeric structure should also give in the
unable to coordinate n-butyllithium: W. B. Marshall, J. L.
Brewbaker and M. S. Delaney, J. Appl. Polym. Sci., 1991, 42
533.
13C NMR spectrum a much less intensive quintet due to 7.6%
natural abundance of 6Li nuclei with I = 1. Note, however,
that in 13C{1H} NMR the signal of the non-deuterated solvent
is quite intensive, which makes it harder to acquire signals of
low intensity and high multiplicity. Apart of the spin-spin
couplings, the width of the signal is also determined by a
quadrupolar relaxation.
,
14 (a) M. Schlosser, Organometallics in Synthesis: A Manual
(2nd ed.) Chichester: J. Wiley and Sons, 2002, 1243 p. (b)
TMEDA is a widely used activator of organolithium
compounds causing their deaggregation. In this connection a
question arises why DMAN as a similar bidentate ligand does 26 U. Schubert, W. Neugebauer and P. von R. Schleyer, J. Chem.
not exert a comparable effect. The point is that the nitrogen Soc., Chem. Commun., 1982, 1184.
atoms in DMAN are located in a rather deep pocket formed 27 S. E. Wheeler, K. N. Houk, P. von R. Schleyer and W. D. Allen,
by four methyl groups and a rigid naphthalene moiety. As J. Am. Chem. Soc., 2009, 131, 2547.
the smallest Lewis acid, only a proton is able to penetrate 28 S. G. Kachalkina, G. S. Borodkin, A. F. Pozharskii, A. S.
relatively easy into this narrow cleft. But even in this case the
protonation-deprotonation rate is by 5–6 orders of ten lower
than that for the common bases such as ammonia, aniline or
Antonov, I. G. Borodkina, Y. F. Maltsev, E. A. Filatova, A.
Filarowski and V. A. Ozeryanskii, Mendeleev Commun., 2015,
25, 182.
pyridine. Therefore other Lewis acids having considerably 29 (a) M. J. Frisch et al. Gaussian 09, Revision B01, Gaussian,
larger ionic radii should form the chelate complexes with
DMAN even more difficulty. To date, complexes of this type
are known only for two elements, except hydrogen: boron
and palladium.1b Their ionic radii are about 5 and 7 times
greater as compared with proton. Though two Pd complexes
were isolated and even subjected to X-ray study, they turned
to be unstable due to the large N–Pd distances. The ionic
Inc., Wallingford CT, 2009. (b) A. D. Becke J. Chem. Phys.,
1993, 98, 5648. (c) C. Lee, W. Yang and R. G. Parr, Phys. Rev.
B, 1988, 15, 785. (d) K. Raghavachari, J. S. Binkley, R. Seeger
and J. A. Pople, J. Chem. Phys., 1980, 72, 650. (e) T. Clark, J.
Chandrasekhar, G. W. Spitznagel and P. von R. Schleyer, J.
Comp. Chem., 1983, 4, 294. (f) M. J. Frisch, J. A. Pople and J.
S. Binkley, J. Chem. Phys., 1984, 80, 3265.
radius of Li is nearly the same as that of Pd. Therefore, in 30 N. V. Vistorobskii and A. F. Pozharskii, Zh. Org. Khim., 1989,
principle, one cannot exclude the possibility of forming 25, 2154. Chem. Abstr. 1990, 112, 234930m.
unstable lithium chelates with DMAN. However, the fact that 31 O. V. Ryabtsova, A. F. Pozharskii, V. A. Ozeryanskii and N. V.
without TMEDA no metallation of DMAN occurs indicates the
absence of any significant chelation of n-BuLi by DMAN.
15 The extremely strong electron-donating resonance effect of 33 G. M. Sheldrick, Acta Cryst., 2008, A64, 112.
Vistorobskii, Russ. Chem. Bull., 2001, 50, 854.
32 APEX2, Bruker AXS Inc., Madison, Wisconsin, USA, 2009.
the peri-NMe2 groups in DMAN is well documented.1b
Another impressive example of such a kind is theoretically
predicted
bis(dimethylamino)-1,8-naphthyridine
a
highly increased basicity
of 4,5-
I.
N,N’-dioxide:
Despotović and R. Vianello, Chem. Commun., 2014, 50
,
10941.
16 Compound
8 was also prepared in a separate experiment by
refluxing 2-Li-DMAN with excess of n-BuBr and its identity
with the sample isolated from the reaction of
was confirmed (see the Experimental Section).
17 V. Snieckus, Chem. Rev., 1990, 90, 879.
7 with n-BuLi
18 On August 2015, the CSD reported four X-ray structures of
lithiumnaphthalenes (Ref.19) and only one of them was 2-
lithiumnaphthalene derivative.19c
19 (a) J. Betz, F. Hampel and W. Bauer, Org. Lett., 2000, 2, 3805.
(b) J. Betz, F. Hampel and W. Bauer, J. Chem. Soc., Dalton
Trans., 2001, 1876. (c) J. Clayden, R. P. Davies, M. A. Hendy,
R. Snaith and A. E. H. Wheatley, Angew. Chem., Int. Ed.,
2001, 40, 1238.
20 Normally, the DMAN molecule and a great majority of its
derivatives exist in a conformation with two unshared
nitrogen electron pairs pointing each other (in,in-form).2 The
less favourable (by 4.7 kcal/mol) in,out-form with one out-
10 | Dalton Trans., 2015, 00, 1-3
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Dalton Transactions
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DOI: 10.1039/C5DT02482J
ARTICLE
A set of X-ray, multinuclear NMR and DFT approaches was used to address a question of selectivity, relative stability and enhanced
reactivity of ring lithiated 1,8-bis(dimethylamino)naphthalenes.
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Dalton Trans., 2015, 00, 1-3 | 11
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