Lithium hexamethyldisilazide/triethylamine-mediated ketone enolization: Remarkable rate accelerations stemming from a dimer-based mechanism

Article abstract of DOI:10.1021/ja021284l

Mechanistic studies of the enolization of 2-methylcyclohexanone mediated by lithium hexamethyldisilazide (LiHMDS; TMS₂NLi) in toluene and toluene/triethylamine (Et₃N) mixtures are described. Structural studies of LiHMDS/ketone mixtur

Full text of DOI:10.1021/ja021284l

Published on Web 03/14/2003
Lithium Hexamethyldisilazide/Triethylamine-Mediated Ketone Enolization:
Remarkable Rate Accelerations Stemming from a Dimer-Based Mechanism
Pinjing Zhao and David B. Collum*
Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell UniVersity,
Ithaca, New York 14853-1301
Received October 21, 2002; E-mail: dbc6@cornell.edu·
The long-held belief that strongly coordinating solvents neces-
sarily accelerate organolithium reactions due to intervening de-
aggregations is not altogether logical.1 We illustrate the point with
a truism: High reaction rates stem from selectiVe stabilization of
the rate-limiting transition structures relatiVe to the reactants. It
follows that reaction rates should be maximized in solvents showing
little or no affinity for the reactants and a high affinity for the
transition structure(s). It is unclear why strongly coordinating
solvents would be so discriminating. Nevertheless, a preoccupation
with highly Lewis basic solvents has practical consequences. For
example, whereas solvents perceived to be strongly coordinating
are prominent in organolithium chemistry,1 poorly coordinating2
trialkylamines have been abandoned by all but a few polymer
chemists.3-5 The lithium hexamethyldisilazide (LiHMDS)-mediated
enolization illustrated in eq 1 suggests that trialkylamines deserve
further evaluation. The rate studies described herein reveal that the
acceleration imparted by Et3N stems from a dimer-based mechanism
(Scheme 1). In contrast, the slower enolization in THF appears to
derive from a monomer-based mechanism.6,7
Figure 1. 6Li NMR spectrum of [6Li,15N]LiHMDS (0.10 M in pentane) at
-120 °C showing complexation by ketone 1-d3 (0.2 equiv) and Et3N (3.0
equiv).
The highly solvent-dependent enolization is best understood in
the context of the low reactivity of LiHMDS in neat toluene.
Treatment of freshly recrystallized LiHMDS8 (0.05-0.30 M) in
toluene with low concentrations of ketone 1 (0.004 M; IR: 1722
cm-1) affords LiHMDS-ketone complex 3 (1707 cm-1) quantita-
tively.9 Complex 3 was fully characterized using [6Li,15N]LiHMDS
Figure 2. Plot of kobsd versus [Et3N] in toluene for the enolization of 1-d3
(0.004 M) by LiHMDS (0.10 M) at -78 °C. The curve depicts the results
of an unweighted least-squares fit to kobsd ) a[Et3N]/(1 + b[Et3N]).
Scheme 1
6
and well-established Li and 15N NMR spectroscopies.10,11 Using
in situ IR spectroscopy to follow the loss of 3 and its 2,6,6-
trideuterated analogue (3-d3) reveals first-order decays and a large
kinetic isotope effect (kobsd(H)/kobsd(D) ) 10 ( 1 at -40 °C).12 In
conjunction with a first-order dependence on [3], a zeroth-order
dependence on [LiHMDS] indicates that enolization proceeds via
a dimer-based transition structure such as 5 (Scheme 1).13,14
Enolization of ketone 1 by LiHMDS/Et3N mixtures also proceeds
via a dimer-based mechanism. The conversion of complex 3 at low
[Et3N] to 4 at elevated [Et3N] is accompanied by a characteristic
6
downfield shift15 of the Li resonance corresponding to the Et3N-
solvated Li nucleus (Figure 1).16 The Li spectrum also includes
the primary product, mixed dimer 7.11,17 IR spectroscopy reveals
that the ketone remains complexed to the lithium of 4 even at high
[Et3N]. Monitoring the enolization using IR spectroscopy reveals
a first-order loss of 4 and a substantial isotope effect (kobsd(H)/kobsd(D)
) 5 ( 1 at -78 °C). A plot of kobsd versus [Et3N] (Figure
6
6
2) displays saturation kinetics consistent with recalcitrant conversion
of 3 to 4. A zeroth-order dependence on [Et3N] and [LiHMDS] (at
high [Et3N]), in conjunction with the first-order loss of 4, indicates
that dimer 4 reacts via a monosolvated-dimer-based transition
9
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J. AM. CHEM. SOC. 2003, 125, 4008-4009
10.1021/ja021284l CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
structure.
Acknowledgment. We thank the National Institutes of Health
for direct support of this work, as well as DuPont Pharmaceuticals
(Bristol-Myers Squibb), Merck, Pfizer, Aventis, R. W. Johnson,
and Schering-Plough for indirect support. P.Z. thanks Boehringer-
Ingelheim for direct support in the form of a partial fellowship.
Supporting Information Available: Spectroscopic and rate data
(PDF). This material is available free of charge via the Internet at http://
pubs.acs.org.
The spectroscopic and rate studies are consistent with dimer-
References
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Si)2NLi}2(1)(Et3N)]q; previous computational studies offer structural
details depicted in Scheme 1, including evidence of the terminal
solvation in 6.14b The large Et3N-mediated rate acceleration appears
to derive from severe steric effects affiliated with solvation in the
reactant that are alleviated in the transition structure. The promotion
of open dimer-based enolizations by sterically hindered ligands was
foreshadowed by semiempirical calculations14 and is supported by
ongoing investigations of other LiHMDS/R3N combinations.7
Enolizations under more synthetically relevant conditions reveal
some interesting subtleties. For example, enolization using 1.0 equiv
of LiHMDS/Et3N (1:5) is approximately 80 times slower than
enolization under pseudo-first-order conditions. The inhibition
observed at the outset of the reaction cannot derive from autoin-
hibition by mixed dimer 7 - the mixed dimer appears only as the
reaction proceeds18 - but rather from the formation of doubly
complexed dimer 8 and the accompanying loss of steric acceleration.
Indeed, enolizations using 2.0 equiv of LiHMDS/Et3N (1:5) -
conditions affording appreciable concentrations of mono-complexed
dimer 4 and mixed dimer 7 (the product of enolization) - are nearly
as fast as the enolizations under pseudo-first-order conditions.
Although it may seem counterintuitive, organolithium reactions can
be inhibited by either the substrate19 or the product.18
In conclusion, the marked rate accelerations stemming from
poorly coordinating solvents and aggregate-based pathways do not
follow conventional wisdom. It may seem odd that a rate accelera-
tion affiliated with a poorly coordinating solvent does not derive
from a pathway involving a desolvation step. Nonetheless, these
observations are fully consistent with the simple notion that solvent-
dependent rate accelerations, whether by weakly or strongly
coordinating ligands, derive from selectiVe stabilization of the
transition state relatiVe to the ground state. On a practical note, the
possible synthetic (and economic) importance of LiHMDS/Et3N
and the more generic RLi/R3N mixtures in hydrocarbons warrants
further investigation.20
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6
operating at 58.84 MHz: (a) 3-d3, Li NMR δ 1.77 (t, JLi-N ) 4.0 Hz),
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6
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with Me3SiCl/Et3N mixtures.
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