Method of continuous variation: Characterization of alkali metal enolates using 1h and 19F NMR spectroscopies

Article abstract of DOI:10.1021/ja504365z

The method of continuous variation in conjunction with ¹H and ¹⁹F NMR spectroscopies was used to characterize lithium and sodium enolates solvated by N,N,N,N-tetramethylethyldiamine (TMEDA) and tetrahydrofuran (THF). A strategy developed using lithium enolates was then applied to the more challenging sodium enolates. A number of sodium enolates solvated by TMEDA or THF afford exclusively tetramers. Evidence suggests that TMEDA chelates sodium on cubic tetramers.

Full text of DOI:10.1021/ja504365z

Article
pubs.acs.org/JACS
Open Access on 06/10/2015
Method of Continuous Variation: Characterization of Alkali Metal
1
19
Enolates Using H and F NMR Spectroscopies
Laura L. Tomasevich and David B. Collum*
Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell University , Ithaca, New York 14853-1301, United States
S
* Supporting Information
1
ABSTRACT: The method of continuous variation in conjunction with H and 19F
NMR spectroscopies was used to characterize lithium and sodium enolates solvated by
N,N,N′,N′-tetramethylethyldiamine (TMEDA) and tetrahydrofuran (THF). A
strategy developed using lithium enolates was then applied to the more challenging
sodium enolates. A number of sodium enolates solvated by TMEDA or THF afford
exclusively tetramers. Evidence suggests that TMEDA chelates sodium on cubic
tetramers.
suspect owing to potentially undetectable impurities.18,19
INTRODUCTION
■
Diffusion-ordered NMR spectroscopy (DOSY) explored
Carbon−carbon bond formations using metal enolates are
extensively by Williard20 in organolithium chemistry could be
ubiquitous. A recent survey of large-scale procedures carried
brought to bear on organosodium chemistry, but no such
out over several decades at Pfizer revealed that 44% of these
studies have been reported to date. Of course, computational
C−C bond formations involved metal enolates.1 Although
chemists have attempted to fill in the experimentally elusive
lithium enolates dominate the field, metal enolates bearing a
details,21 but computational data offer only a complement to,
wide range of counterions proliferate.2 Sodium enolates, for
not a substitute for, experimental data.22
example, are suggested to be decidedly more reactive than their
We wondered whether the method of continuous variation
lithium counterparts.2f However, they are less commonly used
(MCV)23 could be used to characterize sodium enolates. The
in synthesis for several reasons. The lower stability and
idea is simple: mixing two salts of unknown aggregation states
solubility of n-butylsodium3 (n-BuNa) and sodium amides4
denoted as An and Bn (eq 1) affords an ensemble of homo- and
when compared with n-butyllithium and lithium amides make
heteroaggregates manifesting spectroscopic fingerprints and
sodium enolates less accessible. Only weakly basic sodium
concentration dependencies that are highly characteristic of the
hexamethyldisilazide,5 sodium alkoxides,6 and sodium hydride
overall aggregation number, n. We have used such a strategy in
are used routinely. Moreover, empirical studies have suggested
6
conjunction with Li NMR spectroscopy to characterize more
that, with few exceptions,7 the putative greater reactivity
than 100 enolate−solvent combinations.24
imparted by sodium relative to lithium frequently comes at the
cost of lower selectivity. Nonetheless, sodium enolates maintain
An + Bn ⇒ An + An−1B1 + An−2B2 + An−3B3 ... + Bn
an important niche.8,9
(1)
We became interested in studying the influence of
Can this same strategy be used with sodium enolates?
Certainly not using 23Na NMR spectroscopy but possibly with
a more NMR-friendly nucleus. We took a cue from the seminal
study of Gagne and co-workers in which 1H NMR spectroscopy
was used to characterize an ensemble of tetrameric aggregates
derived from sodium tert-butoxide and sodium phenolates
(Scheme 1; Ar = 4-tert-butylphenyl).25 This strategy, combined
with detailed studies of their concentration dependencies with
the application of MCV, could be used to characterize sodium
enolates.
aggregation and solvation on the reactivity of sodium enolates
with the aim of providing structural and mechanistic support to
synthetic applications. Although few sodium enolates have been
characterized crystallographically,10 there is no reason to doubt
that further progress can be made. X-ray structures of sodium
phenolates (isostructural analogues of enolates) reveal a
dominance of cubic tetramers,11 although other forms have
occasionally appeared.12 The challenge of determining solution
structures is acute, however. The absence of detectable M−O
scalar coupling that plagues all NMR spectroscopic studies of
metal enolates is exacerbated by the highly quadrupolar 23Na
nucleus,13 rendering the broad sodium resonances of little or
no diagnostic value.14,15 In what were ambitious and pioneering
studies by Zook16 and Hauser,17 colligative measurements of
relatively stable sodium enolates suggested that they aggregate
in solution, but the measured aggregation numbers are
noninteger values spanning a wide range. In general, colligative
measurements are poorly suited for mixtures and can be highly
1
We describe herein the use of MCV in conjunction with H
and 19F NMR spectroscopies to determine the aggregation state
of alkali metal enolates. To develop tactics and strategies, we
examined lithium enolates (Chart 1) with well-documented
solution structures and behaviors demonstrated in previous
Received: May 1, 2014
Published: June 10, 2014
© 2014 American Chemical Society
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Scheme 1
(NaICA)3 has been prepared as a crystalline TMEDA solvate32
(which we consider too restrictive). We found, however, that
unsolvated NaICA can be prepared as a powder and
recrystallized to >90% purity. NMR spectra of NaICA
solubilized with TMEDA show two forms, which we presume
to be cis and trans cyclic dimers based on analogy to lithium
isopropylcyclohexylamide.33 The only contaminant is the protic
amine (<5%), which may be generated during NMR sample
preparation. The protocols that we used for preparing ligand-
free NaICA and NaHMDS as well as an improved procedure to
prepare LiHMDS are described in the Experimental Section.
General Strategy. Alkali metal enolates are prone to
aggregate as illustrated generically in Chart 3.34 The
Chart 1
studies.24 We then applied the same methods to characterize
the sodium enolates in Chart 2, focusing on synthetically
important N,N,N′,N′-tetramethylethylenediamine (TMEDA)
and tetrahydrofuran (THF) solvates. Several sodium pheno-
lates are included owing to their ease of preparation and
convenient tagging with fluoro moieties as well as their central
roles in pharmaceutically important O-alkylations.26 1H NMR
spectroscopy proves more effective than 19F NMR spectroscopy
in most instances.27 Despite an emphasis in this study on
methods, even the preliminary results revealed that the least
stable sodium enolates 15 and 16 are structurally complex in
THF, and TMEDA-solvated enolates are quite different for
sodium and lithium.28
Chart 3
Chart 2
oppressively high symmetry, which causes these structural
forms to appear deceptively simple and indistinguishable by
NMR spectroscopy, is exacerbated when scalar coupling (such
as 6Li−15N and 6Li−13C) cannot be used to show metal−ligand
connectivities. We break the high symmetry by generating
ensembles of homo- and heteroaggregates from enolate
subunits A and B as illustrated in eq 1. Monitoring the
homo- and heteroaggregates versus mole fraction of subunits A
and B (XA and XB) reveals a distribution in which the number,
symmetries, and mole fraction dependencies are characteristic
of the aggregation state. Application of MCV affords what is
referred to colloquially as a Job plot.23 Subsequent examples are
illustrative.
The prominent technical challenge is to obtain adequate
spectroscopic resolution of the enolate ensembles. Li NMR
6
RESULTS
■
Sodium Bases. We sought sodium bases with optimal
solubilities and reactivities. Highly reactive sodium bases such
as n-BuNa3 and sodium diisopropylamide (NDA)4 present
challenging technical problems. NDA can be prepared directly
from sodium metal29 but is most often prepared from n-BuLi/t-
BuONa metal exchange.3b,30 The solubility properties of
solvated or ligand-free NDA rendered recrystallization difficult,
and the potential complexity arising from the mixed-salt
protocol was especially troubling. Sodium tetramethylpiper-
idide reported by Mulvey may work well but was not tested.4,31
We settled on two bases. The highly soluble NaHMDS is easily
prepared and purified.2,4 It is often the base of choice, but it is
insufficiently basic for some applications (especially cyclo-
alkanone-derived enolates). Sodium isopropylcyclohexylamide
spectroscopy suffices for lithium enolates and has been
exploited extensively.24 Sodium enolates, by contrast, require
the monitoring of resonances emanating from organic frag-
1
ments using H or 19F NMR spectroscopies (19) rather than
the monitoring of a nucleus within the O−M aggregate core.
The obvious advantage of monitoring the vinyl proton (19;
red) is that it requires no explicit tag. We were concerned at the
outset (albeit incorrectly) that resolution might be inadequate
and, in some cases, that complex splitting by other protons
would be problematic. 19F NMR spectroscopy offered the
potential for high resolution but required that at least one
enolate contains a fluoro moiety (19; blue).
19F NMR Spectroscopy. The methods for determining
1
aggregation states are identical for H or 19F NMR spectros-
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Figure 1. 19F NMR spectra of a 1:1 mixture of tetrameric lithium phenolates 2 (A) and 3 (B) at 0.10 M total phenolate concentration in 0.50 M
THF/toluene. The envelope of resonances corresponds to subunit A (left) and subunit B (right). The color code indicates affiliation with the five
homo- and heteroaggregates shown above.
copy. We illustrate them with 19F NMR spectroscopy using an
ensemble generated from phenolates 2 and 3 that both contain
a fluorine tag. Having tags on both enolates is by no means
necessary, but this starting point is pedagogically useful.
Lithium phenolates 2 and 3 prove to be tetrameric and well
behaved. Figure 1 shows the 19F NMR spectrum of an
approximate 1:1 mixture of 2 and 3. We refer to groups of
resonances stemming from a single subunit (A or B) as
envelopes. The two discrete envelopes of four resonances
correspond to four of the five tetrameric aggregates containing
that particular 19F tag in each envelope; one complementary
homoaggregate is missing from each envelope. Accounting for
the number of 19F nuclei per aggregate affords the relative
aggregate concentrations and reveals that the aggregate
distribution reflected by Figure 1 is nearly statistical. The
slight difference between the two envelopes results in part from
a minor deviation from the intended 1:1 stoichiometry.
Seemingly systematic changes in the chemical shifts in Figure
1 with the shifting composition are common but somewhat
deceptive; the chemical shift orderings of the resonances vary
with different enolate pairings.
Monitoring the ensemble of aggregates represented in Figure
1 versus enolate mole fractions (XA or XB) at a fixed total
enolate concentration reveals the changing aggregate propor-
tions (Figure 2). Plotting the relative aggregate concentrations
versus XA affords the Job plot in Figure 3.35 The relative
concentrations are determined by accounting for the differential
number of 19F nuclei per aggregate. When, as in this case, both
subunits contain visible and well-resolved envelopes of
resonances, simply adding the integrations for each aggregate
from the two envelopes of resonances is expedient. The
parametric fits shown have been described previously.24 The
mole fraction, XA, is what we call the measured mole fraction
the mole fraction derived from the relative integrations rather
than the intended mole fractions. Ascertaining the mole
fraction from the integrations renders the method robust by
Figure 2. 19F NMR spectra of mixtures of tetrameric lithium
phenolates 2 (A) and 3 (B) at 0.10 M total phenolate concentration
in 0.50 M THF/toluene. The envelopes of resonances correspond to
subunit A (left) and subunit B (right). The color code indicates
affiliation with the five homo- and heteroaggregates shown above. XA
corresponds to the measured mole fraction ascertained from the
relative integrations.
providing more accurate values for XA as well as eliminating
problems arising from unwanted impurities, standard exper-
imental error, and multiple aggregation states. Using the
measured mole fraction is optional in this application but
becomes imperative when one of the subunits is NMR-silent
(vide infra).
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Figure 3. Job plot showing the relative concentrations of tetrameric
homo- and heteroaggregates versus measured mole fractions of 2 (XA)
for 0.10 M mixtures of lithium phenolates 2 (A) and 3 (B) in 0.50 M
THF/toluene at −80 °C. (See Figure 2.) All aggregates are
represented by summing the integrations of each aggregate within
the two envelopes of resonances.
The example above exploits two envelopes of resonances to
view a single ensemble of aggregates, but this degeneracy is
neither required nor necessarily desirable. Often only one of
two envelopes is well-resolved. More important, we envisioned
the potential of using 19F NMR spectroscopy to probe the
structures of unfluorinated enolates. Using a single envelope of
resonances, however, markedly impacts how the data are
processed in ways that demand careful elaboration. We
illustrate the point using a mixture of phenolates 1 and 3 in
which only 3 has a fluorine tag. Monitoring the ensemble
illustrated in Figure 4 versus mole fraction affords the Job plot
in Figure 5. The logic is described as follows.
Figure 4. 19F NMR spectra of lithium phenolates 1 (A) and 3 (B) at
0.10 M total concentration in 0.50 M propylamine/toluene at −80 °C.
Only B contains a fluorine, rendering A4 spectroscopically invisible.
Given any aggregation state, n, there will be a total of n + 1
homo- and heteroaggregates but only n of them will be visible
owing to the NMR silence of one homoaggregate. The left-
hand y-intercept in Figure 4 corresponds to the measured mole
fraction XA = 0; enolate A is absent. In the limit of high A,
however, the Job plot becomes more abstract. As XA
approaches unity and the spectroscopically silent A4 homoag-
gregate becomes dominant, the only remaining observable
species is the A3B1 heteroaggregate. As the real mole fraction of
A approaches unityas the added B becomes very lowthe
concentration of A3B1 approaches zero in the limit, but the
relative concentration of A3B1 among the observable aggregates
approaches unity. Moreover, the measured mole fraction XA in
Figure 4 necessarily approaches only 0.75 because it represents
the measured mole fraction of A among the spectroscopically
observable aggregates.
Admittedly, the treatment in Figure 5 has some abstraction.
The good news is that the Job plot of a tetrameric enolate
missing one homotetramer is visually and mathematically
similar to a Job plot corresponding to that of a trimer24,36 and
that pattern holds true for all aggregates: n-mers take on the
visual appearance and are mathematically treated as (n − 1)-
mers. The mathematical treatment for all aggregates is fully
developed.24 The asymmetry in Figure 5 is caused by a minor
deviation from statistical behavior. The maxima in Figure 5 are
all found at the appropriate measured mole fraction
corresponding to their stoichiometries, consistent with standard
Job plots.23
Figure 5. Job plot showing the relative integrations of tetrameric
homo- and heteroaggregates versus measured mole fractions of 1 (XA)
for 0.10 M mixtures of lithium phenolates 1 (A) and 3 (B) in 0.50 M
propylamine/toluene at −80 °C. (See Figure 4.) The relative
concentrations include corrections for the number of 19F nuclei in
each aggregate. The curves result from a parametric fit.
1
1H NMR spectroscopy. Ensembles monitored using H
NMR spectroscopy are treated as described above. We illustrate
the point using sodium enolates, for which 1H NMR
spectroscopy proved especially successful. Figure 6 shows
representative spectra in which envelopes of resonances derived
from sodium enolates 11 and 13 are well-resolved. Although
unnecessary in this case, single-frequency decoupling is
occasionally needed to sharpen the resonances. The Job plot
derived from the two pairs of sodium enolates is shown in
Figure 7.
Lithium Enolates and Phenolates. The results for the
lithium enolates and phenolates used to develop the protocols
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Table 1. Characterization of Lithium Phenolates and
1
Enolates in Solution Using 19F and H NMR Spectroscopies
1
Figure 6. H NMR spectra of sodium enolates 11 (A) and 13 (B) at
0.10 M total concentration in 0.50 M TMEDA/toluene-d8 at varying
XA recorded at −80 °C.
a
Typically recorded using 5.0 equiv of ligand in toluene as the bulk
b
solvent. Only 3 was visible in the 19F NMR spectrum, resulting in
singly tagged Job plots. In all other instances, both substrates were
visible, affording Job plots showing all aggregates.
Sodium Enolates and Phenolates. We used exclusively
1H NMR spectroscopy to characterize sodium enolates solvated
by TMEDA and THF (Table 2) owing to the surprisingly poor
resolution using 19F NMR spectroscopy. A representative
example is shown in Figures 6 and 7 above.
Table 2. Sodium Enolate Tetramers Characterized Using the
Method of Continuous Variation and 1H NMR Spectroscopy
a
substrate pairs An/Bn
ligand
10/16
11/13
12/15
13/14
10/11
11/12
11/13
11/14
17/18
TMEDA
THF
Figure 7. Job plot showing the relative concentrations of tetrameric
homo- and heteroaggregates versus measured mole fractions of 11
(XA) for 0.10 M mixtures of sodium enolates 11 (A) and 13 (B) in
0.50 M TMEDA/toluene-d8 at −80 °C. The relative concentrations
are obtained by simply summing the integrations of each aggregate
represented in the two envelopes of resonances. (See Figure 6.).
a
Typically recorded using 5.0 equiv of ligand in toluene as the bulk
solvent.
are listed in Table 1. The spectra and affiliated Job plots are
archived in Supporting Information. Previous studies using Li
6
TMEDA-solvated enolates showed a penchant for forming
NMR spectroscopy in conjunction with MCV have revealed the
structures of the enolates in Chart 1 (except 6 and 9). In several
instances, the high sensitivity of 19F NMR spectroscopy allowed
us to detect a previously undetected minor ensemble. Despite
the large chemical shift window, the 19F resonances broaden at
low temperature and do not resolve. For cases in which one of
the two envelopes of resonances did not resolve, the unresolved
envelope could be integrated, and the contribution from the
second homoaggregate was extracted to provide a standard Job
plot showing all species. In practice, this trick works for dimers
but is challenging for tetramers.
tetramers rather than the anticipated dimers (although in some
cases an additional aggregate could be detected).37 We
demonstrated that TMEDA was bound as an η2 (chelated)
rather than η1 (unchelated) ligand by showing that Me2NEt
and Me2N-n-Bu, which are nonchelating TMEDA surrogates,
failed to mimic TMEDA by affording intractable structures.
Whether all sodium nuclei within a cube are chelated by
TMEDA is discussed below.
The results for simple cycloalkanones were confusing at the
outset. Enolization of cyclohexanone and cyclopentanone using
either NaHMDS/TMEDA or NaICA/TMEDA afforded
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enolates 15 and 16 (Figure 8a). By contrast, enolization with
NaHMDS/THF afforded no detectable enolate, and enoliza-
moieties or have vinyl proton resonances that afford well-
resolved envelopes of resonances when paired with any enolate
regardless of how spectroscopically unfriendly it might be.
Indeed, monitoring one envelope showing four of the five
tetrameric aggregatesone homoaggregate is spectroscopically
invisibleaffords an accompanying Job plot showing the four
visible forms versus mole fraction (Figure 5). Although the Job
plot in Figure 5 is that of a tetrameric ensemble of lithium
phenolates 1 and 3, the missing aggregate renders it visually
comparable to an ensemble of trimers, and it is treated as such
mathematically. The nuances of the analysis are described in
the Results section.
1H versus 19F NMR Spectroscopy. We examined 19F
NMR spectroscopy assuming that we might achieve superior
1
spectroscopic resolution. H NMR spectroscopy, by contrast,
requires no explicit tagging of the substrates and ironically
offers better resolution to that of 19F NMR spectroscopy. In
fact, sodium enolates could only be characterized using H
NMR spectroscopy. The comparison of the enolates herein is
by no means comprehensive; the fluorine tags, admittedly
positioned in relatively remote locations, have offered few
advantages so far.
Figure 8. 1H NMR spectra recorded on 0.10 M 15 generated from 1.0
equiv NaICA in ligand/toluene-d8 solution. The ligands are as follows:
(a) 5.0 equiv TMEDA, (b) 5.0 equiv THF, and (c) 5.0 equiv THF
with addition of 5.0 equiv TMEDA subsequent to enolization.
1
tion with more basic NaICA/THF yielded broad mounds in the
1H NMR spectra (Figure 8b). Treating the cycloalkanones with
NaICA/THF and subsequently adding TMEDA, however,
afforded the TMEDA solvates cleanly (Figure 8c), showing that
enolizations in THF are adequate, but structural control is
poor. The origins of the structural complexity are unknown at
this point.
TMEDA-Solvated Sodium Enolates. In contrast to
lithium enolates in which TMEDA invariably affords chelated
dimers from a wide range of enolates,24,38 the corresponding
sodium enolates in Chart 2 proved to be tetrameric without
exception. Putative unchelated (η1) and chelated (η2) enolates
are illustrated in Chart 4. The small lithium nucleus forces the
Chart 4
DISCUSSION
■
Summary. We undertook a series of structural studies of
alkali metal enolates using MCV in conjunction with H and
1
19F NMR spectroscopies. Lithium enolates known from
previous studies to give high structural control were used to
develop the methods (Chart 1) and distinguish failed strategies
from failed chemistry. We then directed our attention to the
more challenging sodium enolates (Chart 2), which are
emblematic of metal salts bearing metal nuclei that resist
NMR spectroscopic examination.
By example, a 1:1 mixture of two fluorine-tagged enolates
afford two envelopes of 19F resonances highly characteristic of
an ensemble of enolate tetramers (Figure 1). Each envelope
shows four of the five homo- and heteroaggregates; the fifth is
unobservable because it lacks that particular tag. Monitoring the
relative aggregate concentrations versus mole fraction (X)
affords a series of spectra (Figure 2) and an affiliated Job plot
showing the relative concentrations of all five tetrameric forms
(Figure 3). Using 1H NMR spectroscopy to monitor the
enolate vinyl resonance affords analogous envelopes of
resonances (Figure 6) and Job plots (Figure 7). The implicit
assumption in all studies is that the formation of a near-
statistical distribution of homo- and heteroaggregates reflects
the structures of the homoaggregates from which the ensemble
derives. Previous studies of lithium enolates have shown that
two homoaggregated enolates with different aggregation (dimer
and tetramer, for example) either resist forming heteroag-
gregates altogether or form heteroaggregates nonstatistically,
which leads to the maxim “like aggregates with like.″
choice of η2-solvated dimers (akin to 22) over the only
sterically accessible tetrameric form, η1-solvated cubic Li−X
tetramers (akin to 21).39 By contrast, the much larger sodium
nucleus appears to support a chelated TMEDA on cubic Na−X
tetramers (20) as evidenced in crystal structures.40 The chelate
is further evidenced by complete failures of Me2NEt or Me2N-
n-Bu−TMEDA analogues lacking the capacity to chelateto
afford anything tractable. The plot seemed to thicken when
(1R,2R)-N,N,N′,N′-tetramethyl-1,2-cyclohexanediamine
(TMCDA), a TMEDA analogue that appears to be incapable of
forming η1 complexes, afforded intractable results. Either
TMEDA serves a dual role as an η1 and η2 ligand (23) or
TMCDA suffers from other problems related to bite angle or
steric demands.41
Although the clearest examples stem from enolate pairs in
which both subunits can be monitored spectroscopically, this is
neither required nor our intent. Our long-term goal is to
develop a library of enolates that either are tagged with fluoro
THF-Solvated Sodium Enolates. Characterizations of the
sodium indenolates solvated by THF proceeded smoothly. By
contrast, the two generic homoaggregates of sodium enolates
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derived from cyclohexanone (15) and cyclopentanone (16)
afforded broad mounds corresponding to the enolate vinyl
protons. Although we initially thought that the enolization by
sodium bases in THF had gone afoul, enolizations in THF/
toluene with subsequent addition of TMEDA afforded
TMEDA-solvated tetramers indistinguishable from samples
prepared in TMEDA/toluene. Therefore, the broad mounds
attest to structural complexityoligomerizations via enolate
laddering12,42 or cube stacking may be occurring12rather than
decomposition during enolization. The consequences in
synthesis are unknowable but possibly substantial.9 These
results also attest to (albeit only qualitatively) the relative
efficacy of TMEDA to coordinate to sodium.
CONCLUSIONS
■
We have shown that by monitoring NMR-friendly nuclei in the
organic fragment, we can use MCV to characterize sodium
enolates. Those characterized to date illustrate primarily proof
of principle. Nevertheless, the results suggest that the putative
high reactivities of sodium enolates have structural foundations
distinct from their lithium counterparts. After years of studying
organolithium chemistry, we have to extrapolate the principles
derived from lithium to sodium with caution. Fundamental
issues such as rigorously determined solvation numbers have
yet to be addressed. Most important, we do not have a clue
how many principles of structure and reactivity are shared by
lithium and sodium salts. Are the synthetically less central
sodium salts worth the effort and resources? Can principles of
aggregation and solvation unlock potential applications of
sodium enolates? We shall see.
NaHMDS. Isoprene (8.0 mL, 80 mmol) was dissolved in 30 mL of
dry DMEA and added over 1−2 h via syringe pump to a solution of
sliced sodium metal (3.7 g, 160 mmol) and HMDS (25.8 g, 33.4 mL,
160 mmol) in 80 mL DMEA at room temperature. The reaction was
run in the bottom of a swivel fine frit apparatus with 250 mL round-
bottom flasks, attached directly to a Schlenk line (picture). The
temperature was maintained below 30 °C to avoid darkening. If the
cold solution turned yellow, then HMDS had been consumed, and the
addition of isoprene addition was stopped immediately to avoid
further darkening. After addition of isoprene a significant amount of
sodium remained; the reaction was stirred for an additional 2−3 h.
The apparatus was flipped, the solution was slowly filtered, and the
solution was evaporated to dryness under vacuum for 6 h. The white
solid was transferred to a coarse frit setup under inert atmosphere.
NaHMDS was recrystallized from a minimum amount of DMEA
(∼30−50 mL), crystallized by cooling slowly in dry ice/acetone, and
filtered to remove the residual liquid. This procedure was repeated
three times or until the solid was completely white and spectroscopi-
cally pure.5
NaICA. Isoprene (16 mL, 160 mmol) was dissolved in 30 mL dry
DMEA and added over 1−2 h via syringe pump to a solution of finely
sliced sodium metal (7.36 g, 320 mmol) and cyclohexylisopropylamine
(45.2 g, 320 mmol) in 80 mL DMEA at room temperature. Sodium
dispersion is reportedly necessary to acquire a reasonable yield;4 we
sliced the sodium thinly under inert atmosphere and obtained an
acceptable amount of NaICA. The reaction was run in a 250 mL
round-bottom flask attached directly to a Schlenk line. Addition of
isoprene resulted in a yellow solution and precipitation of the product.
After the addition of isoprene was complete, the reaction was stirred
for an additional 6−8 h and evaporated to dryness. A portion of the
solid was transferred under an inert atmosphere to a fine-frit swivel
apparatus (see LiHMDS synthesis figure) and dissolved in DMEA.
The apparatus was flipped, and the solution was slowly filtered, then
the solution was evaporated to dryness. In a glovebox, approximately 3
g of the off-white solid was added to each of two centrifuge tubes fitted
with a stopcock for eventual compaction of a very fine powder.
(Substantial crude solid remained for future crystallization.) Under
continuous argon flow, the solid was dissolved in DMEA and
concentrated to the point of turbidity. Cyclopentane (25 mL) was
EXPERIMENTAL SECTION
■
Reagents and Solvents. All substrates are commercially available.
TMEDA, THF, and toluene were distilled from blue or purple
solutions containing sodium benzophenone ketyl. Owing to the
appearance of vinyl ethers from tetraglyme degradation in the 1H
NMR spectra, no tetraglyme was added to dissolve the ketyl in
toluene, resulting in a lighter blue color. Liquid substrates were
distilled from 4 Å molecular sieves. (Some ketones decompose on
exposure to molecular sieves for extended times.) NaHMDS,4
NaICA,4,32 and [6Li]LiHMDS43 were prepared and recrystallized
from modified literature procedures as described below. Air- and
moisture-sensitive materials were manipulated under argon using
standard glovebox, vacuum line, and syringe techniques.
[6Li]LiHMDS. Isoprene (8.0 mL, 0.080 mol) was dissolved in 30
mL dry dimethylethylamine (DMEA) and added over 1−2 h via
syringe pump to a solution of lithium metal (1.11 g, 0.16 mol) and
hexamethyldisilazane (HMDS, 25.8 g, 33.4 mL, 0.16 mol) in 80 mL
DMEA at room temperature. The reaction was run in the bottom of an
apparatus with 250 mL round-bottom flasks and a fine frit attached
directly to a Schlenk line (inset). The temperature was maintained
below 30 °C to avoid darkening. If the solution turned yellow at low
temperature, the HMDS was consumed, and isoprene addition was
stopped immediately to avoid further darkening. After the addition of
isoprene, the mixture was stirred until the lithium metal was nearly
consumed (up to 1 h). The apparatus was inverted to filter the
solution, and then the solution was evaporated to dryness under
vacuum for 6 h. DMEA had to be removed completely because it
provides the LiHMDS with too much added solubility in the
subsequent pentane recrystallization. The white solid was transferred
to an analogous coarse frit setup in a glovebox and returned to the
Schlenk line. LiHMDS was dissolved in a minimum amount of
pentane, crystallized slowly at −78 °C, and filtered to remove the
residual liquid. This procedure was repeated three times or until the
solid was completely white. The solid was spectroscopically pure as
described previously.43
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Journal of the American Chemical Society
Article
added, and the vessel cooled with dry ice/acetone. The resulting
suspension was centrifuged to form a white cake, and the supernatant
was removed via syringe. This procedure was repeated until the
supernatant was colorless. The resulting white solid was dried under
vacuum. Full NMR spectroscopic characterization included COSY,
TOCSY, HSQC, HMBC, and ROESY spectroscopies (Supporting
Information). 13C{1H} NMR (125 MHz, 0.50 M TMEDA/toluene-d8)
δ (isomer 1) 23.36, 27.08, 28.33, 39.04, 49.08, 80.92; (isomer 2) 25.73,
26.52, 28.05, 34.13, 43.72, 52.81 ppm.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Spectral data and Job plots. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
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Corresponding Author
dbc6@cornell.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Institutes of Health (GM077167) and
Sanofi−Aventis for direct support of this work.
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