From monomeric tBuLi-(R,R)-TMCDA to α-lithiated (R,R)-TMCDA

Article abstract of DOI:10.1002/anie.200702116

(Chemical Equation Presented) The α-lithiation of amines by direct deprotonation has to date only been possible in a few systems. The enantiomerically pure amine (R,R)-TMCDA coordinates to tBuLi to form a monomeric molecular structure. Starting from tBuLi-(R,R)-TMCDA, lithiation of the ligand occurs, which results in a trimeric α-lithiated amine (see picture).

Full text of DOI:10.1002/anie.200702116

Angewandte
Chemie
DOI: 10.1002/anie.200702116
Lithium Alkyl compounds
From Monomeric tBuLi·(R,R)-TMCDA to a-Lithiated (R,R)-
TMCDA**
Carsten Strohmann* and Viktoria H. Gessner
Lithiated hydrocarbons are known for their distinctive
tendency to form oligomeric aggregates.[1] Nevertheless, in
reactions like deprotonations, monomeric structures are
usually assumed to be the reactive species in commercially
available saturated alkyl lithium compounds. To date, only a
single such monomer, tBuLi·(ꢀ)-sparteine (1), could be
isolated and characterized by single crystal
reacting groups approach one another spatially is formed by
pre-coordination. This reaction pathway (or this pre-coordi-
nation) is called the complex-induced proximity effect
(CIPE).[7] Assuming such a thermodynamically favorable
pre-coordination of tBuLi to (R,R)-TMCDA, as we propose
herein, deprotonation of a methyl group should be possible.
Monomeric tBuLi·(R,R)-TMCDA (3) crystallizes from an
equimolar solution of tert-butyllithium and (R,R)-TMCDA in
n-pentane at ꢀ788C as colorless needles in the monoclinic
crystal system in the space group P21.[8] Apart from
tBuLi·(ꢀ)-sparteine (1), 3 is the only structurally character-
ized monomeric alkyl lithium compound bearing a saturated
X-ray structure analysis.[2] The sterically
demanding ligand (ꢀ)-sparteine prevents
the formation of higher aggregates. Like
sparteine, the C2-symmetric (1R,2R)-
N,N,N’,N’-tetramethylcyclohexane-1,2-dia-
mine [(R,R)-TMCDA, (R,R)-2],
a
less
hydrocarbon.[2] Similar to 1, tBuLi·(R,R)-TMCDA has shorter
[9,10]
ꢀ
demanding ligand, is used in asymmetric
Li C bonds [2.064(15) Š] than dimeric compounds.
deprotonation.[3] In light of these properties,
However, as the space-filling model of 3 shows (Figure 1)
the sterically less demanding nature of the ligand (R,R)-
TMCDA leaves a positively polarized coordination site at the
lithium center quite exposed. This site of attack explains the
high reactivity of tBuLi·(R,R)-TMCDA. During preparation
of the crystals, 3 proved to be significantly more reactive than
1 or (tBuLi)4, and in toluene solution it deprotonated the
methyl group of toluene at ꢀ308C.
we wondered what structure is formed by
(R,R)-TMCDA and tBuLi. In the course of
the ensuing investigations, we observed the unexpected a-
lithiation of (R,R)-TMCDA, which can be explained by
assuming
a monomeric tBuLi·(R,R)-TMCDA precursor.
Recently, we suggested a different reaction pathway for the
a-lithiation of N,N,N’,N’’,N’’-pentamethyldiethylentriamine
(PMDTA) on the basis of the molecular structure of
[(nBuLi)2·PMDTA]2.[4]
a-Lithiated amines are usually only accessible by trans-
metalation or through the more readily deprotonated amino-
boranes.[5] The synthesis of a-lithiated amines by direct
deprotonation usually requires intramolecular activation,
which can take place through a second nitrogen center.
Examples of such a-lithiated di- and triamines are PMDTA,
On warming from ꢀ788C to room temperature, a
suspension of tBuLi and (R,R)-TMCDA in n-pentane
becomes clear at about ꢀ308C. From this temperature on,
slow lithiation of the ligand can be observed. The reaction of
the solution formed at room temperature with MePh2SiCl
yields compound 5, the silylated reaction product of a-
lithiated (R,R)-TMCDA. No carbenoid behavior of the
lithiated nitrogen compound was evident. From an analo-
gously prepared reaction solution of tBuLi and (R,R)-
TMCDA in pentane at ꢀ788C, a-lithiated (R,R)-TMCDA 4
N,N,N’,N’-tetramethylethylenediamine
(TMEDA),
and
N,N,N’,N’-tetramethylmethylenediamine (TMMDA).[6] The
repulsive interaction between the carbanion and the free
electron pair on the nitrogen atom is often offered as
explanation for the hindered metalation. These interactions
can, however, only be employed as an argument for transition
states close to the products. In contrast, a two-stage process is
usually assumed for deprotonation in the presence of donor
centers; in the first step, a reactive intermediate in which the
[*] Dr. C. Strohmann, V. H. Gessner
Institut für Anorganische Chemie, Universität Würzburg
Am Hubland, 97074 Würzburg (Germany)
Fax: (+49)931-888-4605
E-mail: mail@carsten-strohmann.de
[**] We thank the Deutsche Forschungsgemeinschaft and the Fonds der
Chemischen Industrie (FCI) for the financial support of this work
and the FCI for a postgraduate fellowship.
Figure 1. Left: molecular structure and numbering scheme for tBuLi·
(R,R)-TMCDA (3).[11] Selected bond lengths [Š] and angles [8] (for one
of the two molecules in the asymmetric unit): C11-Li 2.064(15), Li-N1
2.086(15), Li-N2 2.055(11); C11-Li-N2 134.1(6), C11-Li-N1 135.6(7),
N2-Li-N1 87.4(5). Right: space-filling model.
Supporting information for this article is available on the WWW
under http://www.angewandte.com or from the author.
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(Scheme 1) crystallizes as a trimer in the orthorhombic crystal
differently arranged molecular groups should result in such
broadened or overlapping signals.[1]
ꢀ
system in the space group P212121 (Figure 2). The Li C
distances of compound 4 vary between 2.140(11) and
Why is (R,R)-TMCDA lithiated? The otherwise difficult
a-lithiation is facilitated in monomeric tBuLi·(R,R)-TMCDA
(3) by the spatial proximity of the reacting groups, in
agreement with the CIPE concept.[7] Quantum-chemical
studies at the B3LYP/6-31 + G(d) level (Figure 3) confirm
this interpretation with a calculated reaction barrier of only
98 kJmolꢀ1 for the intramolecular metalation of TMCDA
starting from monomeric tBuLi·(R,R)-TMCDA. Slow metal-
ation below room temperature would be anticipated from
these energy barriers.
2.265(11) Š and thus lie in the region of monomeric and
dimeric compounds.[2,9,10] The same is true for the Li N
ꢀ
distances; each lithium center is closer to the nitrogen center
attached to the lithiated carbon atom [1.942(9)–1.992(10) Š]
and further away from the second nitrogen center [2.085(10)–
2.182(10) Š]. [(R,R)-TMCDA-Li]3 is one of only few trimeric
alkyl lithium compounds.[12] Without addition of Lewis bases,
alkyl lithium compounds preferentially exist as hexameric or
tetrameric aggregates. Variable-temperature NMR spectros-
copy studies with a solution of 4 in [D8]toluene showed highly
broadened signals between ꢀ80 and 208C in both the
1H NMR and the 13C NMR spectra. Both dynamic processes
and freezing of the unsymmetric trimeric structure with three
Figure 3. Transition state of the metalation of (R,R)-TMCDA in the
monomeric aggregate with tBuLi; B3LYP/6-31+G(d).[13]
a-Deprotonation of a methyl group has also been
described for TMEDA, which raises the question as to
whether other structurally related diamines also undergo
deprotonation of their methyl group.[5a–c] For achiral N,N’-
dimethylpiperazine, we were also able to elucidate a molec-
ular structure with tBuLi in the solid sate, but no deproto-
nation was observed in solution. The coordination polymer
[(tBuLi)2·(N,N’-dimethylpiperazine)]1 (6) crystallizes with an
additional half molecule N,N’-dimethylpiperazine from an
equimolar solution of tBuLi and the ligand in n-pentane at
ꢀ308C in the form of colorless needles in the triclinic crystal
Scheme 1. Formation of monomeric tBuLi·(R,R)-TMCDA (3) and its
reaction to a-lithiated (R,R)-TMCDA (4).
¯
system in the space group P1 (Figure 4). The coordination
polymer consists of central tert-butyllithium dimers, which are
coupled to further dimers through two ligand molecules to
form a coordination polymer. In this structure, the N,N’-
dimethylpiperazine molecules are orientated at right angles
to one another, thus creating a zigzag arrangement of the
chains. Compound 6 is the first coordination polymer of
tBuLi, which on account of its spatial demand otherwise
forms smaller aggregates.[2,9b]
Why is N,N’-dimethylpiperazine not lithiated by tBuLi?
On the basis of the molecular structure of 6, deprotonation
starting from either a dimeric aggregate or a monomer should
be open to discussion. Whereas monomeric tBuLi·(R,R)-
TMCDA is 14 kJmolꢀ1 more favorable than 0.25(tBuLi)4 and
(R,R)-TMCDA, 36 kJmolꢀ1 are required for the formation of
monomeric tBuLi·N,N’-dimethylpiperazine starting from 0.25
(tBuLi)4 and N,N’-dimethylpiperazine, which cannot be
compensated by entropic effects. Nevertheless, if the forma-
tion of the monomeric model compound tBuLi·N,N’-dime-
Figure 2. Molecular structure and numbering scheme for [(R,R)-
TMCDA-Li]3 (4).[11] Selected bond lengths [Š] and angles [8]: C1-Li1
2.171(11), C1-Li2 2.265(11), C21-Li2 2.140(11), C21-Li3 2.148(10), C11-
Li3 2.159(11), C11-Li1 2.187(11), Li1-N3 1.973(12), Li1-N4 2.182(10),
Li2-N1 1.942(9), Li2-N2 2.153(11), Li3-N5 1.992(10), Li3-N6 2.085(10);
Li1-C1-Li2 96.7(4), Li3-C11-Li1 81.7(4), Li2-C21-Li3 81.7(4), C1-Li1-C11
143.4(5), C21-Li2-C1 136.6(5), C11-Li3-C21 137.7(5).
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Chemie
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Figure 4. Molecular structure and numbering scheme for
[(tBuLi)2·(N,N’-dimethylpiperazine)]1 (6).[11] Selected bond lengths [Š]
and angles [8] (for clarity, the additional half molecule of N,N’-
dimethylpiperazine was omitted): C1-Li1 2.244(5), C1-Li2 2.212(4), C5-
Li1 2.224(4), C5-Li2 2.228(5), Li1-N1 2.191(5), Li2-N2’ 2.158(6), Li1-Li2
2.357(6); Li1-C1-Li2 63.86(16), Li2-C5-Li1 63.93(15), C1-Li1-C5
109.25(17), C5-Li2-C1 110.27(19), C1-Li2-Li1 58.74(16), C5-Li2-Li1
57.94(15).
thylpiperazine is assumed, a-lithiation involves overcoming a
barrier of 131 kJmolꢀ1. Deprotonation starting from the
dimeric model compound (tBuLi·N,N’-dimethylpiperazine)2
gives an energy barrier of 132 kJmolꢀ1, which might be
reduced by 10 kJmolꢀ1 released by the formation of the dimer
from 0.5(tBuLi)4 and two N,N’-dimethylpiperazine.[14,15] Thus,
N,N’-dimethylpiperazine is not lithiated by tBuLi, because
monomeric molecular structures or transition states are only
poorly stabilized and a corresponding transition state in a
dimer also lies too high energetically.
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[11] CCDC-645928 (3), CCDC-645929 (4) and CCDC-645927 (6)
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from the Cambridge
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request/cif.
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Whether or not a-lithiation of methylamines occurs can
be explained on the basis of the molecular structures
presented. In monomeric tBuLi·(R,R)-TMCDA (3), the
carbanionic carbon atom and the H atom of the methyl
group approach each other, which facilitates a-lithiation of
(R,R)-TMCDA. Such a spatial proximity is not reached in
[(tBuLi)2·(N,N’-dimethylpiperazine)]1 (6). Since the break-
down into smaller aggregates requires too much energy and
possible reaction barriers are too high, no lithiation of N,N’-
dimethylpiperazine can take place. We are currently search-
ing for further di- and triamines which, owing to their good
coordination properties and the associated formation of
reactive intermediates with spatially preorientated reacting
groups, may be deprotonated.
Received: May 14, 2007
Revised: July 12, 2007
Published online: September 26, 2007
Keywords: chirality · lithiation · lithium alkyl compounds ·
.
N ligands · quantum chemical calculations
[13] Gaussian03 (RevisionB.04), M. J. Frisch et al., Gaussian, Inc.,
Pittsburgh, PA, 2003. See the Supporting Information for the
complete author list.
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