Enantiodivergence in the reactions of a highly enantiomerically enriched silyllithium compound with benzyl halides: Control of inversion and retention by selection of halide

Article abstract of DOI:10.1002/anie.200352700

Inversion of the configuration at the silicon center is observed for the reaction of benzyl bromide with the highly enantiomerically enriched silyllithium compound 2. In contrast, retention of configuration occurs at the silicon center with benzyl chlorid

Full text of DOI:10.1002/anie.200352700

Angewandte
Chemie
Stereochemistry
first reactions of an optically active silyllithium compound
with organic electrophiles—is reported in the following.
Racemic silyllithium compounds react with chlorosilanes
in good yields with the formation of disilanes. In contrast,
reactions with alkyl halides give only modest yields, which
probably accounts for why these reactions have aroused only
Enantiodivergence in the Reactions of a Highly
Enantiomerically Enriched Silyllithium
Compound with Benzyl Halides: Control of
Inversion and Retention by Selection of Halide**
Carsten Strohmann,* Martin Bindl,
Verena C. Fraaß, and Jan Hörnig
The reaction behavior of optically active silyllithium
compounds was first described and investigated in
detail by Sommer et al.[1] and later by Corriu et al.[2]
and Kawakami et al.[3] The absolute configurations of
the investigated compounds 1 and 2 were stable at
room temperature. Their reactions with H2O and
H2O/HCl gave the respective hydridosilanes with
retention at the silicon center. It was deduced from
these results that “silyl anions” react with electro-
philes under retention.[4]
An alternative synthetic route by means of tin–
lithium exchange has been described for 2 as has the
racemization of 2 and 3 in solution.[3] The only
reactions of enantiomerically enriched silyllithium
compounds with chlorosilanes have been carried out
Scheme 1. Products of the reactions of the highly enantiomerically enriched compound 4
with benzyl chloride (retention) and benzyl bromide (inversion). The assignment of the
stereochemical pathways relates to the disilane(S)-5 used.
little interest.[6] This is partly attributable to the observ-
À
able coupling products (disilanes and products of C C
couplings) which can be the consequence of halogen–
lithium exchange reactions.[7] These side reactions may be
partially suppressed by lithium–copper exchange, but the
respective silyl cuprates usually show an altered regiose-
by Kawakami et al. and our group.[3,5] Kawakami et al.
described retention of configuration but in this work it was
not made clear by the authors how the absolute configura-
tions were unambiguously assigned and how these conclu-
sions were reached. By our route the highly enantiomerically
enriched silyllithium compound 4 (Scheme 1) is accessible
which racemizes within a few hours at room temperature in
THF. However, at low temperatures the resulting 4 reacts
further with chlorosilanes selectively with retention starting
from (R)-5 and (S)-5, respectively.[5] The aminomethyl sub-
stituent allows resolution of the disilane (S)-5 and simplifies
analysis of the silanes investigated. The unexpected stereo-
chemical reaction courses of the highly enantiomerically
enriched silyllithium compound 4 with benzyl halides—the
lectivity.[8] We therefore asked ourselves how the highly
enantiomerically enriched silyllithium compound 4 reacts
with benzyl halides and whether the stereochemical probe at
the silicon center can provide information on the course of the
reaction.
A solution of 4 was freshly prepared by cleavage of the
unsymmetrical disilane (S)-5 with lithium at À788C (it
contains a molar equivalent Ph2MeSiLi; see Scheme 1). A
solution of 4 in THF[5] was added to the respective benzyl
halide in THF (2.6 equivalents relative to (S)-5) at different
temperatures. After warming to room temperature the
product composition of the respective reaction mixture was
determined before and after workup by GC-MS and NMR
spectroscopy, and the enantiomeric ratios were determined by
1H NMR spectroscopy in the presence of (S)-mandelic acid.
À
Assuming that the Si Si bond of (S)-5 is cleaved with
[*] Priv.-Doz. Dr. C. Strohmann, M. Bindl, V. C. Fraaß, J. Hörnig
Institut für Anorganische Chemie
retention (see reference [5]) the reaction of 4 with benzyl
chloride leads to benzylsilane (S)-6 with retention. The
analogous reaction with benzyl bromide yields in contrast
the benzylsilane (R)-6 with inversion.
Universität Würzburg
Am Hubland, 97074 Würzburg (Germany)
Fax: (+49)931-888-4605
E-mail: mail@carsten-strohmann.de
The assignment of the absolute configurations of (S)-6 and
(R)-6 was carried out by single-crystal X-ray structure
analysis of the methiodide (S)-7 (Scheme 2).[9] Compound
(S)-7 was synthesized on the one hand from an enantiomeri-
cally pure sample of (S)-6 obtained by repeated recrystalliza-
tion as hydrochloride (Scheme 2, path (a)), and on the other
[**] We thank the Deutsche Forschungsgemeinschaft, the Graduierten-
kolleg 690, and the Fonds der Chemischen Industrie for financial
support of this work and Wacker-Chemie GmbH for providing us
with special chemicals.
Supporting information for this article is available on the WWW
under http://www.angewandte.com or from the author.
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DOI: 10.1002/anie.200352700
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Scheme 4. Proposed mechanism for the observed stereochemical
reaction pathway of inversion with benzyl bromide.
Scheme 2. Synthesis of enantiomerically pure (S)-6 and methylation to
(S)-7: a) recrystallization as hydrochloride, release with NaOH; b) res-
olution with di-O-4-toluoyl-d-tartaric acid, recrystallization as hydro-
chloride, release with NaOH.
mechanism with SET steps, and a mechanism with inter-
mediate ate complexes. Experimental evidence has been
described for both mechanisms. Several reports suggest that
the courses of the reactions are highly associated with the type
of electrophile, which greatly impairs a study of this mech-
anism.[13] Quantum-chemical studies of Boche et al. on
methyl-ate complexes suggest that ate complexes are pivotal
intermediates in halogen–lithium exchange reactions with
alkyllithium compounds.[13e] Experimental and theoretical
studies of Hoffmann et al. as part of the synthesis of optically
active alkylmagnesium compounds show that ate complexes
are also involved in iodine–magnesium exchange reactions
with alkylmagnesium compounds.[13a–c]
In order to support the proposed mechanisms for our
experimental observations (SN2 mechanism and halogen–
lithium exchange via an ate complex) DFT calculations
(B3LYP/6-31 + G(d)) were carried out on the model system
H3SiÀ/ClCH2Ph and H3SiÀ/BrCH2Ph (Figure 1).[14] The meth-
ods for the description of the relevant stationary
from an enantiomerically pure sample of (S)-6 prepared by
resolution (Scheme 2, path (b)). Solutions prepared from
single crystals of (S)-7 measured by X-ray structure analysis
exhibited the same rotation for linearly polarized light as the
solutions of the respective enantiomerically pure total
material.
With the assumption that the cleavage of the disilane (S)-5
to 4 takes place with retention and formation of the anion (R)-
8, two different reaction mechanisms can be proposed as
explanation for the unusual stereochemical courses: the
À
formation of the Si C bond in the reaction of 4 or (R)-8
with benzyl chloride follows an SN2 mechanism under
substitution of chloride at the benzylic carbon center with
retention of configuration at the silicon center (Scheme 3). In
points have been discussed comprehensively in a
quantum-chemical study on the SN2 mechanism
published recently.[12] Since SN2 reactions in the gas
phase and in solution differ because of solvent
effects, calculations with solvent models are neces-
sary. The stationary points were energy optimized
in THF solution by means of the self-consistent
reaction field (SCRF) method based on the On-
Scheme 3. Proposed mechanism for the observed stereochemical reaction pathway of reten-
tion with benzyl chloride. (Due to the change of substituents the priorities of CIP nomencla-
ture and thus the absolute configurations are inverted here and in Scheme 4.)
the reaction of 4 or (R)-8 with benzyl bromide, however, a
bromine-lithium exchange occurs first with retention of the
configuration at the silicon center (Scheme 4). The enantio-
merically pure bromosilane (S)-11 then reacts with benzyl-
lithium under inversion of configuration at the silicon center
so that the whole reaction sequence occurs with inversion.[10]
If the first reaction step is sufficiently rapid few or no further
coupling products of the halosilanes, silylithium and alkyl-
lithium compounds should be formed—as observed in the
experiment.[11]
Whereas in reactions with other nucleophiles the SN2
mechanism has already been established,[12] the mechanism of
halogen–lithium exchange reactions is still controversial.[13]
The two extreme cases for the latter reaction are a radical
Figure 1. Molekel plots[16] of the calculated stationary points for the
studied model systems H3SiÀ/ClCH2Ph und H3SiÀ/BrCH2Ph.
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sager model, and the energies for the structures obtained were
also calculated with the polarizable conductor calculation
model (CPCM).[12,15] From the calculations with the CPC
solvent model we obtained the following trends for the model
systems studied (Table 1): in the case of benzyl chloride the
increase the respective selectivities.[8] Leaving group and
temperature are furthermore critical for selective reactions
with the silyllithium compound 4. Only the stereochemical
probe at the silicon center permitted us to obtain an insight
into the described processes since the products of both
reaction pathways differ merely in their absolute configura-
tion at the silicon center. Currently we are investigating the
question of how further specific influences can be exerted on
the course of the reaction, for example, through choice of
solvent.
Table 1: Relative energies Erel of the calculated stationary points from
Figure 1.
Relative energies Erel [+zero point correction (ZPVE)] [kJmolÀ1
]
Method
TS-1/Br
TS-2/Br
MIN-1/Br
TS-1/Cl
TS-2/Cl
Onsager
CPCM[a]
19.3
9.5
0
0
À27.2
À38.4
0
0
1.0
12.9
Methods
The calculations were carried out with Gaussian98,[14] energy
minimizations and calculations were carried at the B3LYP/6-31 +
G(d) level with Cs symmetry. The SCRF method based on the
Onsager model (e = 7.58 for THF) was used for structure optimiza-
tion and energy calculation. Single point energy calculations were
carried out by means of CPCM for the stationary points minimized
with the Onsager model. Zero-point corrections were obtained from
the frequency calculations with the Onsager model. The transition
states exhibited in each case exactly one imaginary frequency in the
direction of the expected reaction coordinate. Because of the low
rotational barriers of the SiH3 groups a further weak imaginary
frequency was found in each case for TS-1/Cl, TS-1/Br, and TS-2/Cl
which are attributed to this process (see also lit. [13e] for related
systems). Absolute electronic energies are collated in Table 3.
[a] The energy values for zero-point correction (ZPVE) are derived from
the frequency calculations with the Onsager model.
transition state TS-2/Cl for a chlorine–lithium exchange lies
about 12.9 kJmolÀ1 higher than the alternative path through
direct substitution of the halogen (TS-1/Cl). However, for
benzyl bromide these energy relationships are reversed, and
the bromine–lithium exchange (TS-2/Br) is favored by
9.5 kJmolÀ1 over the substitution (TS-1/Br). Likewise, the
ate complex MIN-1/Br can be characterized as a minimum.
We were unable to localize an analogous ate complex for
benzyl chloride. The DFT calculations on the model systems
thus showed the trends observed in the experiment (Table 1).
The small energy difference between the respective
stationary points suggests a significant temperature depend-
ency for the reaction of 4 with benzyl chloride and benzyl
bromide. It emerged in the investigation that indeed in these
reactions the resulting enantiomeric ratios were critically
dependent upon the reaction temperature (Table 2), whereby
Table 3: Absolute electronic energies of the quantum-chemical calcu-
lations in atomic units.
Structure
E according to Onsager[a]
E according to CPCM
TS-1/Br
TS-2/Br
MIN-1/Br
TS-1/Cl
TS-2/Cl
À3134.00838976 (0.138686)
À3134.01539512 (0.138354)
À3134.02585360 (0.138438)
À1022.47347412 (0.138720)
À1022.47250767 (0.138126)
À3134.06740722
À3134.07068775
À3134.08538291
À1022.53251263
À1022.52701893
Table 2: Relationship between the enantiomeric ratios for the reaction of
4 with benzyl chloride and benzyl bromide and the reaction temperature.
[a] The ZPVE values (in parentheses) for the zero-point correction are
derived from the frequency calculations with the Onsager model.
Trapping reagent
benzyl chloride
T [8C]
(S):(R)
Received: August 22, 2003[Z52700]
0
À40
À78
0
>55:45
83:17
94:6
18:82
8:92
Keywords: benzyl halides · density functional calculations ·
.
benzyl bromide
organosilanes · silyllithium compounds · stereochemistry
À40
À78
5:95
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