Sterically facilitated meta-lithiation of arenes, containing electron-donating groups

Article abstract of DOI:10.1016/j.jorganchem.2019.121068

The influence of the bulky trimethylsilyl substituent on the selectivity of metallation of dimethylaniline, anisole and 1-dimethylaminonaphthalene is studied. The neighboring SiMe₃ group forces dimethylamino and methoxy groups to occupy a confo

Full text of DOI:10.1016/j.jorganchem.2019.121068

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Sterically facilitated meta-lithiation of arenes, containing electron-donating groups
Alexander S. Antonov, Victor G. Bardakov, Valeria V. Mulloyarova
PII:
S0022-328X(19)30511-X
DOI:
https://doi.org/10.1016/j.jorganchem.2019.121068
JOM 121068
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 6 September 2019
Revised Date: 11 November 2019
Accepted Date: 4 December 2019
Please cite this article as: A.S. Antonov, V.G. Bardakov, V.V. Mulloyarova, Sterically facilitated meta-
lithiation of arenes, containing electron-donating groups, Journal of Organometallic Chemistry (2020),
doi: https://doi.org/10.1016/j.jorganchem.2019.121068.
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Sterically facilitated meta-lithiation of arenes, containing electron-donating
groups
Alexander S. Antonov*,1 Victor G. Bardakov1 and Valeria V. Mulloyarova1
1Institute of Chemistry, St. Petersburg State University, Universitetskii pr. 26, 198504 St. Petersburg,
Russian Federation
e-mail: aleksandr.antonov@spbu.ru
ABSTRACT: The influence of the bulky trimethylsilyl substituent on the selectivity of metallation of
dimethylaniline, anisole and 1-dimethylaminonaphthalene is studied. The neighboring SiMe3 group
forces dimethylamino and methoxy groups to occupy a conformation with an unshared electron pair
turned towards silicon atom. This forced conformation prevents NMe2 and OMe groups from providing
the DOM-effect, thus facilitating meta-metallation with the use of bulky LiCKOR. While the inverted
NMe2 group completely suppresses ortho-metallation, the less bulky and more electron withdrawing
OMe group demonstrates more rotation freedom allowing selective ortho-metallation with smaller
reagents such as n-BuLi or tert-BuLi.
INTRODUCTION
It is widely known that arenes containing electron donating groups with unshared electron pairs
undergo selective ortho-metallation due to the so-called Direct Ortho-Metallation (DOM) effect.[1] Thus
N,N-dimethylaniline 1, anisole 2 and fluorobensene 3 are selectively metallated to the ortho-position
upon treatment with n-butyllithium in ethers in the presence of N,N,N,N-tetramethylethylenediamine
(TMEDA), which gives corresponding aryllithiums 4-6 with good to high yields (scheme 1).[2–4]
Scheme 1.
The situation dramatically changes in the case of related naphthalene derivatives 7-9. The lithiation of
1-dimethylaminonaphthalene 7 leads to the formation of a peri-lithio derivative 12 with high yield, while
fluoronaphthalene 9 undergoes exclusively ortho-lithiation.[4,5] Methoxynaphthalene 8 occupies an
intermediate position: depending on the conditions, it can be lithiated to either the ortho- or peri-
position, thus demonstrating competition between the higher CH-acidity of the H-2 atom and the higher
stability of the five-membered metallocycle (scheme 2).[6]
1

Scheme 2.
The metallation of 1,8-bis(dimethylamino)naphthalene (DMAN, proton sponge) 14 is especially
surprising because it leads to the formation of a meta-lithioderivative 15 as the main product in all cases
(scheme 3).[7,8] It has been proven that the preferable in/in conformation of NMe2 groups is responsible
for this issue: it prevents the realization of the DOM-effect and sterically hinders the C2(7)-H bond from
deprotonation by bulky reagents.[8]
Scheme 3.
The above-mentioned phenomenon raises the question on whether or not the direct selective meta-
functionalisation of arenes containing electrondonating groups can be achieved by the sterical hindering
of the DOM-effect. This is especially desirable since reactions of such substrates with electrophiles yield
mostly ortho- and para-substituted products.[9] Here we present our experimental and theoretical study
on the influence of bulky trimethylsilyl groups in the ortho- or peri-position on the metallation of
methoxy and dimethylamino benzenes and naphthalenes.
RESULTS AND DISCUSSION
We started our experiments with the preparation of thrimethylsilyllated arenes 16-18 through the
treatment of lithioarenes 4, 5 and 12 with trimethychlorosilane (scheme 4). It was expected that the
sterical pressure of the bulky substituent will force the methoxy and especially the dimethylamino group
to occupy the conformation with unshared electron pairs turned to the silicon atom (in-conformation),
and thus being unable to provide the DOM-effect.
2

Scheme 4.
Since all obtained trimethylsilylarenes are liquids, their X-Ray study was not possible. Instead, we
performed gas phase quantum chemical calculations in order to confirm our expectation on the
structure of the studied substrates (Figure 1). Indeed, the maps of the electron localization function
maxima (ELF) demonstrate the expected in-conformation with lone pairs turned towards the silicon
atom for all cases. One can assume that this conformation is stabilized by the interaction of nitrogen or
oxygen lone pairs with the silicon empty d-orbital. However, the performed NBO analysis [10] revealed
that there is no such interaction and the silicon d-orbitals remain empty even in the case of amine 18
(see Figure S2 in Supplementary materials). Thus, the mentioned in-conformation is forced and
stabilized only by sterical pressure of the bulky SiMe3 group. We also calculated an optimized geometry
and proton affinities for all possible monoanions of compounds 16-18 in order to compare their CH
acidities (Figure 2, see also Figure S3 in Supplementary materials). One can see that the PA of anions
with a negative charge in the ortho-position to a nitrogen or oxygen atom is 5-10 kcal/mole lower than
for any other isomer.
Figure 1. Optimized molecular structure for compounds 16–18 in vacuo (B3LYP/6-311++G(d,p)). The
electron localization function (ELF) level is shown.
Me
Me
Me
Me
Me
O
N
N
SiMe3
401.6
402.4
SiMe3
406.9
SiMe3
406.3
397.1
405.0
399.9
404.5
395.1
401.4
408.0
17
406.1
16
399.8
400.4
18
Figure 2. Calculated proton affinities (kcal/mole) for anions of compounds 16–18 (B3LYP/6-
311++G(d,p)).
We performed metallation of compounds 16-18 with a mixture of potassium tert-butylate, n-
butyllithium (aka LiCKOR [11]) and TMEDA – a bulky and extremely strong metallation agent, as well as
with n-BuLi-TMEDA and tert-BuLi-TMEDA mixtures. We expected that forced in-conformation would
prevent ortho-to NMe2 group positions from metallation by bulky reagents. In all cases, no evidences of
3

CH bond ortho to the SiMe3 group deprotonation were detected. This corresponds to the experiments
performed by Schlosser and Knochel, who both attributed this phenomenon to the sterical hindrance of
the ortho-CH proton by the bulky SiAlk3 group.[11,12] This statement seems reasonable and to some
extent obvious, however we performed the visualisation of electron density isosurfaces mapped by
electrostatic potential (see Figure S4 in Supplementary materials), which clearly demonstrates that the
CH proton ortho to the SiMe3 group holds the least (among other aromatic CH protons) positive
potential. As a result, this position becomes less favorable for the interaction with the negatively
charged deprotonating agent (carbanionic center of organometallic reagent). Moreover, from the PA
values (Figure 2) one can see that the deprotonation of mentioned CH bonds leads to the formation of
less stable carbanions. Thus, the bulkiness of the SiMe3 group is not the only feature preventing
metalation of the neighbouring CH bonds, and the electron donating nature of this substituent is also to
be considered. Keeping all this in mind, it was expected to observe somewhat selective lithiation of the
CH-bond meta to the NMe2 (or OMe) group, since these protons bear the second most positive charge
and their deprotonation leads to the formation of the second most stable carbanion.
We found that compound 16 yields only products of H-4 and H-5 hydrogens deprotonation upon
treatment with LiCKOR-TMEDA, despite a noticeably higher acidity of the C6-H bond (Scheme 5, Figure
3a). In contrast, N,N-dimethylaniline 1 gives a mixture of all possible products (Scheme 5, Figure 3b)[8]
under same conditions. Switching to the tert-BuLi-TMEDA mixture gives the similar result, however
some unreacted started material remains. The treatment of the amine 16 with an n-BuLi-TMEDA
mixture in Et2O or hexane leads to no metallation even at an elevated temperature. Thus, our
expectations were confirmed: 1) the sterical pressure of the bulky SiMe3 group prevents the NMe2 group
of 16 to occupy an out-conformation, requested for the DOM-effect realization, and 2) the in-
conformated NMe2 group sterically hinders the H-6 atom from deprotonation.
forced in-conformation
Me
Me
Si
Me
N
NMe2
NMe2
sterically
Me
Me
LICKOR,
TMEDA
blocked
Me3Si
Me3Si
+
Li
hexane
-20 oC, 72h
sterically
blocked
19a
16
19b
Li
NMe2
NMe2
Me3Si
+
Me3Si
DMF
CHO
20a
20b
CHO
3.5 : 1
NMe2
NMe2
NMe2
NMe2
LICKOR,
TMEDA
DMF
CHO
+
+
hexane
CHO
-20 oC, 72h
1
CHO
21c
21b
1 : 0.4 : 0.1
21a
Scheme 5.
4

Figure 3. Fragments of 1H NMR spectra (CDCl3) for the reaction mixture after the metallation of
compounds 16 (a, 500 MHz) and 1 (b, 250 MHz) with tert-BuOK, n-BuLi, TMEDA mixture.
Treating of 18, the calculated molecular structure of which is very reminiscent of a proton sponge 14,
with LiCKOR-TMEDA unexpectedly leads to the formation of a complicated mixture of products, which is
very unlikely for 14 but typical for naphthalene [11]. We believe that the higher inertness of the proton
sponge originates from a strong +M-effect provided by two NMe2 groups, which noticeably overcome
their -I-effect. In the case of 18, one NMe2 group obviously provides a less strong +M-effect, thus
facilitating polymetallation. Indeed, switching to the tert-BuLi-TMEDA mixture (less basic than LiCKOR
but also quite bulky) leads to a significant simplification of the reaction mixture and formation of four
aldehydes (after treatment with DMF) 23a-d (Scheme 6, Figure 4). The result of this experiment leads to
two main conclusions: 1) expectedly, the sterical hindrance prevents the deprotonation of H-7 or H-2
hydrogens, 2) the formation of the aldehydes 23a-d originates from the proximity of PA values for the
related anions (Figure 2).
forced in-conformation
Me
Me
sterically
blocked
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
N
Si
Me
N
Si
Me
N
Si
Me
N
Si
N
Si
sterically
blocked
tert-BuLi
TMEDA
Me
Me
+
+
Li
+
hexane
Li
-20 oC, 72h
18
22d
22a
22c
22b
Me
Li
Me
Li
N
Me
Me
DMF
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
N
Si
Me
Si
N
Si
N
Si
Me
Me
Me
+
+
+
CHO
OHC
23c
23a
23d
23b
CHO
CHO
1
:
2
:
4
:
2
Scheme 6
5

Figure 4. Fragment of 1H NMR spectra for the reaction mixture after the metallation of compound 18
with a tert-BuLi, TMEDA mixture (CDCl3, 400 MHz).
Noticeably, the metallation of ether 17 with an n-BuLi-TMEDA mixture in hexane leads to selective H-6
hydrogen deprotonation with 57% conversion over 24 hours (Scheme 7). Switching to a tert-BuLi-
TMEDA mixture gives the same ortho-selectivity, however with 100% conversion. One can assume that
the sterical pressure of the SiMe3 group on the OMe group does not fully hinder the H-6 proton and
leaves an opportunity for the OMe group to coordinate the organometallic reagent, thus providing the
DOM-effect. Indeed, scanning the potential energy surface for the complex of 17 with the LiMe
molecule using the ModRedundant method revealed the possibility for the coordination of an oxygen
atom to lithium when the distance between these atoms reaches ~1.9 Å (Figure 5, see also Figure S5 in
Supplementary materials). However, optimization of molecular geometry of the ortho-lithiated
complexes 26-28 demonstrate that neither OMe nor NMe2 groups undergo rotation/inversion to
coordinate the neighboring lithium atom (Figure 6). Altogether, this data leads to the conclusion that
the selective ortho-metallation of 17 with n-BuLi or tert-BulI originates not from a DOM-effect provided
by the OMe group, but from the highest acidity of the C6-H bond (magnified by the strong -I-effect of
oxygen) which is only moderately hindered by the OMe group and thus accessible for the interaction
with relatively small organometallic reagents.
Me
Si
Me
OMe
O
Me
Me
tert-BuLi
TMEDA
Me3Si
Li
hexane
rt, 24h
24
17
OMe
DMF
70%
Me3Si
CHO
25a
Scheme 7.
6

Figure 5. Optimized molecular structure for the complex of 17 with MeLi (B3LYP/6-311++G(d,p)).
Optimal O-Li distance (Å) is shown.
Figure 6. Optimized molecular structure for the complex of 26-28 with TMEDA (B3LYP/6-311++G(d,p)).
Total energies are shown.
As it was expected, the treatment of 17 with the LiCKOR-TMEDA mixture results in significant meta-
lithiation. Due to relatively high CH-acidity (compared to benzene, or N,N-dimethylaniline) of the
substrate, the resulting mixture is quite complicated. However, through the use of NOESY NMR
spectroscopy, it becomes clear that the main reaction products are ortho-aldehyde 25a and meta-
aldehyde 25b (Scheme 8).
Me
Me
Si
OMe
O
OMe
Me
Me
LICKOR,
TMEDA
Me3Si
Me3Si
CHO
DMF
+
hexane
-20 oC, 72h
CHO
25b
25a
17
1 : 1
Scheme 8.
CONCLUSIONS
7

In summary, it has been proven that the insertion of bulky SiMe3 groups into ortho- or peri-positions to
NMe2 or OMe groups prevents the realization of the DOM-effect. Firstly, the bulky SiMe3 group forces
dimethylamino and methoxy groups to occupy a stable conformation with lone electron pairs oriented
towards the silicon atom, which prevents the effective coordination with lithium. Secondly, methyl
groups of immobilized NMe2 or OMe groups sterically hinder the C2(7)-H bonds from deprotonation by
bulky bases. Thirdly, while ortho-CH-bonds are blocked, the noticeably high acidity of meta-CH bonds
facilitates meta-lithiation.
ASSOCIATED CONTENT
1
Experimental details, quantum-chemical calculations, H, 13C, NOESY and COSY NMR spectra for all
obtained compounds are available in Supplementary Information.
ACKNOWLEDGMENT
This work was supported by the Russian Foundation for Basic Research (project 16-33-60030). NMR
measurements were performed in the Centre for Magnetic Resonance and computations were made in
the Computing Centre at St. Petersburg State University Research Park. The authors thank Mr. Daniel
Raith for proofreading the paper in terms of the English language.
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9

1) Bulky SiMe3 groups in ortho- or peri-positions to NMe2 or OMe groups prevent
realization of the DOM-effect.
2) Methyl fragments of immobilized NMe2 or OMe groups sterically hinder ortho-
CH-bonds from deprotonation by bulky bases.
3) While ortho-CH-bonds are blocked, noticeably high acidity of meta-CH bonds
facilitates meta-lithiation.

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: