Sodium Diisopropylamide: Aggregation, Solvation, and Stability

Article abstract of DOI:10.1021/jacs.7b03061

The solution structures, stabilities, physical properties, and reactivities of sodium diisopropylamide (NaDA) in a variety of coordinating solvents are described. NaDA is stable for months as a solid or as a 1.0 M solution in N,N-dimethylethylamine (DMEA) at 20 °C. A combination of NMR spectroscopic and computational studies show that NaDA is a disolvated symmetric dimer in DMEA, N,N-dimethyl-n-butylamine, and N-methylpyrrolidine. Tetrahydrofuran (THF) readily displaces DMEA, affording a tetrasolvated cyclic dimer at all THF concentrations. Dimethoxyethane (DME) and N,N,N′,N′-tetramethylethylenediamine quantitatively displace DMEA, affording doubly chelated symmetric dimers. The trifunctional ligands N,N,N′,N″,N″-pentamethyldiethylenetriamine and diglyme bind the dimer as bidentate rather than tridentate ligands. Relative rates of solvent decompositions are reported, and rate studies for the decomposition of THF and DME are consistent with monomer-based mechanisms.

Full text of DOI:10.1021/jacs.7b03061

Article
pubs.acs.org/JACS
Sodium Diisopropylamide: Aggregation, Solvation, and Stability
Russell F. Algera, Yun Ma, and David B. Collum*
Baker Laboratory, Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853-1301, United States
S
* Supporting Information
ABSTRACT: The solution structures, stabilities, physical
properties, and reactivities of sodium diisopropylamide
(NaDA) in a variety of coordinating solvents are described.
NaDA is stable for months as a solid or as a 1.0 M solution in
N,N-dimethylethylamine (DMEA) at −20 °C. A combination of
NMR spectroscopic and computational studies show that NaDA is a disolvated symmetric dimer in DMEA, N,N-dimethyl-n-
butylamine, and N-methylpyrrolidine. Tetrahydrofuran (THF) readily displaces DMEA, affording a tetrasolvated cyclic dimer at
all THF concentrations. Dimethoxyethane (DME) and N,N,N′,N′-tetramethylethylenediamine quantitatively displace DMEA,
affording doubly chelated symmetric dimers. The trifunctional ligands N,N,N′,N″,N″-pentamethyldiethylenetriamine and diglyme
bind the dimer as bidentate rather than tridentate ligands. Relative rates of solvent decompositions are reported, and rate studies
for the decomposition of THF and DME are consistent with monomer-based mechanisms.
ethylenediamine (TMEDA), and 1,2-dimethoxyethane
(DME). The cyclic dimer motif (1a−h) is the only detectable
INTRODUCTION
■
Several groups, most recently that of Mulvey, have underscored
the merits of sodium dialkylamides,1,2 but the response of the
synthetic organic community remains muted compared with
the enthusiastic embrace of lithium diisopropylamide (LDA)
and related lithium dialkylamides.3 Sodium diisopropylamide
(NaDA) is an excellent case in point. Since the initial
preparation of NaDA by Levine in 19594 and subsequent
improved preparations,5 NaDA has languished in relative
obscurity, appearing in the literature only a dozen times over
half a century.6 This scarcity is somewhat perplexing on first
inspection. NaDA is easily prepared, stable as a solid if
refrigerated, and a powerful Brønsted base.5,6 We surmised that
potential users must be leery of the rapid destruction of
standard ethereal solvents by NaDA and its insolubility in inert
hydrocarbons. In short, NaDA is inconvenient.
In our first paper of this series, we reported that 1.0 M
solutions of NaDA in neat N,N-dimethylethylamine (DMEA)
or DMEA−hydrocarbon mixtures are stable for weeks at room
temperature and for months under refrigeration.7 Moreover,
NaDA−DMEA can be prepared in 15 min from technical-grade
reagents without pre-purification or pre-drying. Metalations of a
dozen substrates with a broad range of functionality have
shown that NaDA−DMEA is often orders of magnitude more
reactive than LDA−THF toward orthometalations, dehydroha-
logenations, diene metalations, and epoxide eliminations.7 The
stereo- and chemoselectivities of the two bases are often
complementary. Even concerns that the sodiated intermediates
and products in DMEA might be insoluble have proved
unfounded. Overall, the results of our initial studies were highly
encouraging, and, as a reviewer noted, “running reactions in
trialkylamine solvent is not crazy.”
form. DMEA is substitutionally labile, which is a critical
prerequisite for the addition of other ligands before metalation
to modulate the reactivity of NaDA and after metalation to
control reactivity of the resulting sodium salts. Mechanistic
studies of solvent decomposition offer the first glimpse into
NaDA reactivity. This paper is intended to detail the structural
foundations underpinning NaDA structure−reactivity−selectiv-
ity principles of potential interest to synthetic organic chemists.
RESULTS
■
Methods. We modified the dissolving metal method first
described by Wakefield and co-workers5a by using kinetically
inert and solubilizing DMEA as the bulk solvent.5,7 Although
the procedure affords 1.0 M stock solutions of NaDA adequate
In this second paper, we examine the solution structure and
stability of NaDA solvated by DMEA, other trialkylamines, and
a number of synthetically important coordinating ligands
including tetrahydrofuran (THF), N,N,N′,N′-tetramethyl-
Received: March 27, 2017
© XXXX American Chemical Society
A
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for synthetic applications, a precautionary crystallization from
DMEA−hexane was included for spectroscopic and rate
studies. We hasten to add that the typical user will detect little
or no difference between the pre- and post-purified reagent.
Given the absence of resolved 23Na−15N coupling owing to
the quadrupolar 23Na nucleus and with an eye toward
expanding the application of the method of continuous
variations (MCV) to aggregated organometallic species lacking
NMR-active metal nuclei, we turned to MCV to assign the
solution structure.8,9 In short, an ensemble generated from
constitutionally similar species of unknown aggregation number
(An and Bn, eq 1) is monitored with NMR spectroscopy as a
function of mole fraction XA or XB. The number of
heteroaggregates attests to the aggregation state. Plotting the
relative proportions versus mole fraction affords a Job plot
confirming the assignment.
Figure 2, which is characteristic of statistically distributed
dimers.
An + Bn → An + An−1B1 + An−2B2 + ... + Bn
(1)
For this study, NaDA was paired with sodium dicyclohexyl-
amide (NaDCA)5c,10 and sodium isopropylcyclohexylamide
(NaICA).9a NaICA was previously suggested to be dimeric, as
evidenced by two stereoisomers (cis-2 and trans-2, eq 2; Cy =
Figure 1. NMR spectra of a ∼1:1 mixture (0.10 M total titer) of
sodium diisopropylamide (NaDA; 1) and sodium dicyclohexylamide
(NaDCA; 3) in neat dimethylethylamine (DMEA) affording
heterodimer 4. (a) 13C NMR spectrum recorded at −80 °C. (b)
15N NMR spectrum using [15N]NaDA and [15N]NaDCA recorded at
−100 °C.
cyclohexyl).9a We confirmed the dimer assignment for NaICA
and showed that both NaDA and NaDCA are dimers 1 and 3,
respectively, by examining NaDA−NaICA and NaDA−NaDCA
mixtures using 13C and 15N NMR spectroscopies. NaDA−
NaDCA pairings are superior and are emphasized below.
Considerable data for the NaDA−NaICA pairings are archived
1
in the Supporting Information. Although H NMR spectros-
copy proved especially valuable in MCV-based studies of
sodium enolates,9a,11 the resolution was inadequate for the
study of sodium dialkylamide aggregation.
The strategies and quantitative insights into solution
solvation numbers of NaDA are notable in our opinions.
Confirmations and experimentally elusive details are provided
with density functional theory (DFT) computations at the
B3LYP/6-31G(d) level,12 with single-point calculations at the
MP2 level of theory.13
Solution Structure: NaDA in DMEA and Related
Amines. 13C NMR spectra of NaDA−NaDCA mixtures in
DMEA showed the dimer ensemble depicted in eq 3 with
Figure 2. Job plot showing relative integrations of the 13C resonances
of 1 (black), 3 (blue), and 4 (red) versus the measured14 mole fraction
of NaDA (XNaDA) for mixtures of NaDCA and NaDA in neat DMEA
at −80 °C.
A
15N NMR spectrum of a 1:1 mixture of [15N]NaDA and
[15N]NaDCA shows signals corresponding to two homodimers
and a heterodimer distributed statistically (Figure 1b). A Job
plot based on 15N NMR data is analogous to that shown in
Figure 2 (Supporting Information).
MCV analyses using the NaDA−NaICA mixtures (eq 4)
were effective, but they have been largely relegated to
Supporting Information. Several interesting observations are
worth noting, however. The 13C NMR data resolved two
methinyl resonances in each of the two NaICA homodimers as
well as the four methinyl resonances in heterodimer 5 (eq 4),
readily affording the corresponding Job plot. 15N NMR
resolution of all 13C methine resonances of the isopropyl and
cyclohexyl moieties (Figure 1a). A plot of the relative
integrations of 1, 3, and 4 afforded the Job plot illustrated in
B
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value at −80 °C is based on a structural change: low
temperature promotes rather than retards solvation owing to
negative enthalpy. Also, the solubility of NaDA in DMEA is
nearly temperature-independent. The results from THF solvate
1d (see Table 1) are discussed below.
A more traditional probe of solubility provided significant
insight.18 The concentration of DMEA-solubilized NaDA in a
suspension of NaDA in toluene-d8 was monitored as a function
spectroscopy using [15N]NaDA and [15N]NaICA showed that
the 15N resonances of the homo- and heteroaggregated NaICA
fragments are poorly resolved, whereas homo- and hetero-
aggregated NaDA fragments are well-resolved. Poor resolution
on one pair is not critical;9a the resulting Job plot is consistent
with a statistical distribution of dimers.
1
of added DMEA using H NMR spectroscopy and benzene as
an internal standard; the two-phase equilibrium is described in
eq 5.19 If DMEA coordinates to and solubilizes NaDA
quantitatively (Ksolv ≫ 1), the concentration of NaDA will be
proportional to the concentration of DMEA until full solubility
is achieved, with the solvation number being extractable from
the slope and the end point (eq 8). We see this behavior for
superior solvents (vide infra). In the limit of weak binding (Ksolv
≪ 1), the solubility will be low while manifesting curvature
diagnostic of the coordination number (eq 9). The measured
concentration of NaDA in solution versus added DMEA
(Figure 3) showed non-limiting behavior: it is upwardly curving
13C and 15N NMR spectroscopic investigations of the
NaDA−NaDCA pair in N,N-dimethylbutylamine (DMBA)
and N-methylpyrrolidine showed that NaDA is dimeric
(Supporting Information). DFT computations showed that
sequential solvation of dimeric NaDA by DMEA is highly
exothermic and affords disolvate 1a, but no minima
corresponding to tri- or tetrasolvated dimers were found. The
sterically less demanding and computationally simpler Me3N
gave similar results. This outcome contrasts sharply with
ethereal and multidentate ligands (vide infra).
Owing to our experience with DFT computations in lithium
chemistry, we were comfortable with the assignment of 1a as
disolvated. Nonetheless, we applied several experimental
methods to determine the solvation as follows. Proton
diffusion-ordered NMR spectroscopy (1H-DOSY), first applied
to organolithium aggregates by Williard,15 is now proliferating
within the field16 and has been applied to organosodiums.17
Underlying assumptions about molecular shape and influence
on the diffusion constant have always left us uneasy, however.
We examined the structure of NaDA in DMEA using the
double bipolar pulse pair stimulated echo sequence with
convection compensation pulse sequence to measure the
diffusion coefficients of NaDA dissolved in DMEA. An
analogous experiment independently measured diffusion
coefficients for DMEA, THF, tetramethylsilane, anisole, 1,3-
dimethoxybenzene, and 18-crown-6 to obtain the molecular
weights for NaDA shown in Table 1. Although the data
recorded at ambient temperature seemed to confirm the
disolvated dimer, the molecular weight at −80 °C was 25% low.
Similar temperature dependencies have been noted by
others.16,17 We have no evidence, however, that the reduced
Figure 3. Plot of NaDA concentration versus total DMEA
concentration in toluene at room temperature fit to eq 7 and
presuming one DMEA per sodium (solid line, n = 2 [set],20 Ksolv
=
0.072 0.004) and two DMEA per sodium (dashed line, n = 4 [set],
Ksolv = 0.007 0.002).
with a fit to eq 7 showing disolvated dimer (n = 2). Forcing the
model to a tetrasolvated dimer (n = 4) provided a markedly
inferior fit to the data.
Ksolv
(A)solid + nS HoooI (A2Sn)solution
(5)
Ksolv = [A2Sn]/[S]n
(6)
[A2Sn] = Ksolv([S]0 − n[A2Sn])n
(7)
Table 1. Molecular Weight (MW) of Sodium
Diisopropylamide in Dimethylethylamine and
[A2Sn] = [S]0 /n
(8)
1
Tetrahydrofuran Determined with H Diffusion-Ordered
a
n
Spectroscopy
[A2Sn] = Ksolv[S]0
(9)
MW
Thus, recalcitrant solubilization of NaDA by DMEA reflects
weak binding. This notion is reinforced by studies of additional
monodentate trialkylamines (Supporting Information). As
steric demands increase, the binding constant, Ksolv, decreases.
The poor solubility of NaDA in triethylamine, for example,
stems from weak coordination rather than a low solubility of
aggregate
calcd
diffusion, −80 °C
diffusion, rt
1a
1d
393
534
298
565
391
481
a
rt = room temperature.
C
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the doubly solvated dimer. We return to this idea in the
Discussion.
solubilization at 2.0 equiv. This outcome is fully consistent
with tetrasolvate 1d.
The tetrasolvated form is also strongly supported computa-
tionally (eq 10). Given the exothermicity and our experience
that DFT computations tend to falter with congested systems,
we are confident in the tetrasolvate assignment.
Solution Structure: NaDA−THF. MCV using 13C and 15
N
NMR spectroscopies for NaDA−NaICA and NaDA−NaDCA
pairs demonstrated that THF-solvated NaDA is dimeric at both
low and high THF concentrations (Supporting Information).
As usual, determining the solvation state demanded several
strategies. Incremental additions of THF to NaDA in 2.0 M
DMEA (Figure 4) showed clear saturation of the changing
Solution Structure: NaDA−TMEDA. MCV showed that
the solution aggregation state of NaDA−TMEDA is akin to the
reported doubly chelated crystal structure (Supporting
Information).6b We hoped to observe free and bound
TMEDA in the slow-exchange limit to directly measure the
number of ligands on the bound form, but the exchange was
rapid at −100 °C. Two titration methods showed strong
coordination by TMEDA and supported a 1:1 proportion of
NaDA/TMEDA:
(1) Substitution of DMEA by TMEDA was evidenced by a
1
downfield shift of the methinyl H resonance and an
Figure 4. Plot of 15N chemical shifts of 1 versus equivalents of
tetrahydrofuran (THF) in 2.0 M DMEA−hexane at −80 °C.
upfield shift of the 15N resonance after substitution of
TMEDA by DMEA. As found for THF, however, the
stoichiometry of the substitution was obscured by non-
quantitative binding (Supporting Information).19
(2) Titration of a suspension of NaDA with TMEDA
(analogous to that in Figure 5) showed a linear
dependence of the measured titer on TMEDA
concentration, a constant 1:1 proportion of TMEDA to
NaDA in solution up to complete dissolution, and a hard
solubility end point corresponding to 1:1 stoichiometry
of TMEDA/NaDA.
chemical shifts of the methine proton and 15N resonances
resulting from ligand substitution consistent with strongly
preferential THF coordination. However, curvature with
saturation occurring at ∼3.0 equiv of THF per sodium (as
opposed to a linear dependence with a sharp end point) belied
non-quantitative substitution, thereby obscuring the stoichiom-
etry. Fortunately, titration of a suspension of NaDA in toluene,
as described for trialkylamines (Figure 5 and eqs 5−7), revealed
a linear dependence of the measured titer on added THF and a
constant 2:1 THF/NaDA ratio in solution up to full
DFT computations showed that the displacement of DMEA
by chelated TMEDA (eq 11) is exothermic. This result
contrasts with that observed with LDA, which forms a weakly
ligated η1-TMEDA-solvated dimer in solution.21−23
Solution Structure: NaDA−DME. DME acts as an ethereal
analogue of TMEDA in every respect: (1) 13C NMR
spectroscopy in conjunction with MCV showed dimers, (2)
incremental addition (akin to those in Figure 5) to NaDA−
DMEA showed semi-quantitative binding consistent with one
DME per sodium, (3) titration of a NaDA suspension showed a
linear dependence of the titer on DME with a hard solubility
end point at 1:1 stoichiometry, and (4) DFT computations
supported a highly exothermic substitution of DMEA by DME
without MP2 correction. We encountered a unique situation in
which uncorrected energies and geometries corroborated
experiment, yet MP2 correction provided highly questionable
1.6 kcal/mol/Na solvation energies (eq 11) for reasons we
Figure 5. Plot of NaDA concentration versus total THF concentration
for suspensions of NaDA in toluene at room temperature. The
concentration is measured relative to benzene (internal standard).
Inset: Plot of THF/NaDA ratio versus equivalents of THF added to
the anticipated amount of NaDA at room temperature. The
discontinuities correspond to full solubilization.
D
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failed to identify. We explored a variety of larger basis sets with
no obvious improvements. All evidence, including the results of
experimental competition studies, suggested that the MP2
correction is indeed spurious.
THF−hexane mixtures at 25 °C forms partially soluble cis-
1
and trans-alkoxides 7 observable with H NMR spectroscopy
(Scheme 1). Quenching afforded known alcohols 8 and 9 in the
Doubly chelated dimer 1f contrasts with LDA, in which two
DMEs coordinated to the dimer are unchelated.21,24,25 We also
competed TMEDA and DME by swapping one for the other at
a fixed total ligand concentration corresponding to 2.0 equiv
per sodium and monitored the chemical shifts of the time-
averaged free and bound ligand. TMEDA is the stronger ligand
by approximately 10-fold.
Scheme 1. Decomposition of THF
Solution Structure: NaDA with Other Ligands. The
results of 15N NMR spectroscopy and MCV showed that
trifunctional ligands diglyme and N,N,N′,N″,N″-pentamethyl-
diethylenetriamine (PMDTA) afford dimers rather than
monomers that could have arisen from tridentate ligation.
Their binding affinities are slightly greater than those of the
bidentate analogues DME and TMEDA. Thus, these potentially
tridentate ligands function as bidentate ligands, as demon-
strated by 1g and 1h.26,27 Computations suggest that the third
ligand, although not coordinated to sodium as evidenced by
long Na−OMe and Na−NMe2 bonds, display distinct
preferences for orienting the lone pairs toward the sodium
nuclei. We discuss the potential synthetic importance of
bidentate rather than tridentate coordination below.
proportions shown in Scheme 1. The presumed intermediate
salt 6 is observed at low (equilibrium) levels owing to facile
NaDA-mediated isomerization to 7; the isomerization of 6
under the reaction conditions was confirmed by adding 8 to
NaDA−THF-d8.
Monitoring the rate of THF decomposition by tracking the
1
loss of 1d (δ 3.11 ppm in H NMR) and the formation of
diisopropylamine showed that the reaction does not follow a
first-order decay, which indicated that the decomposition does
not occur from the observable dimer. Fitting the traces to the
nonlinear Noyes equation32 afforded an average order of 0.68
(Figure 6), approximating a half order. Plotting initial rates
versus THF concentration revealed a second-order THF
dependence (Figure 7). The half-order rate constants are
nearly independent of the NaDA concentration, albeit with a
slight upward drift (Figure 8). The idealized rate law33 (eq 12)
is consistent with the mechanism described in eq 13.34 Rate-
limiting proton transfer was evidenced by a substantial kinetic
isotope effect determined by comparing THF to THF-d8 (kH/
kD = 6.9).
We carried out a brief survey of a number of ligands that
lacked rigor but provided useful data nonetheless.28 Ethereal
ligands such as Et2O and 2,5-dimethyltetrahydrofuran sub-
stitute for DMEA but much more reluctantly than does THF as
expected from binding measurements on lithium amides.23,26,27
Titration of NaDA/toluene suspensions with anisole displays
chemical shift perturbations consistent with binding but no
appreciable solubilization, suggesting that anisole is a poor
ligand for sodium. The highly dipolar ligand N,N′-dimethyl-
propyleneurea (DMPU) is quickly metalated by NaDA at −80
°C, as evidenced by the rapid appearance of extraneous
1
resonances and diisopropylamine observable with H and 15N
−d[A2(THF)4]/dt = k[A2(THF)4]1/2[THF]2
(12)
NMR spectroscopies. The products of these decompositions
have not been pursued.29
k
1/2 A2(THF)4 + 2THF → [A(THF)4]⧧
Solvent Decomposition: Products, Rates, and Mech-
anisms.30,31 Whether in DMEA or in its solid form, NaDA at
room temperature has a half-life of approximately 2 months,
consistent with the thermal sensitivity noted by Wakefield.6b
This decomposition is mitigated by storage at −20 °C in a
standard laboratory freezer. However, facile decompositions of
DME and DMPU underscore the possible limitations of NaDA
when used in conjunction with standard ethereal solvents. The
stability of NaDA in selected solvents at room temperature is
illustrated in Table 2.
(1d)
(13)
THF decomposition offered our first view of the mechanism
of NaDA-mediated metalations. NaDA decomposition in
Table 2. Approximate Half-Life of 0.30 M NaDA in
Common Laboratory Solvents at Room Temperature
a
ligand
half-life
DMEA
TMEDA
THF
2 months
1 month
1 h
Figure 6. Plot of NaDA concentration versus time for the
decomposition of THF (Scheme 1) of NaDA at 25 °C. The red
curve depicts an unweighted least-squares fit to the function f(t) =
[a1−n − kt/(1 − n)][1/(1−n)], where a = 0.3484 0.0002, k = 1.061 ×
10−5 9 × 10−8, and n = 0.698 0.002.
DME
10 s
b
DMPU
≪1 s
a
b
Neat. 0.30 M DMPU in DMEA.
E
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Scheme 2. Mechanism of THF Decomposition
Figure 7. Plot of initial rates versus THF concentration for the
decomposition of THF (Scheme 1) in 0.20 M NaDA at 25 °C. The
curve depicts an unweighted least-squares fit to the function f(x) = axb
+ c, where a = 0.025 0.008, b = 1.9 0.1, and c = 0.14 0.05.
to Figure 6). Fitting multiple decays to the nonlinear Noyes
equation32 to ascertain the order by best fit affords an average
order of 0.52. Plotting the half-order rate constants versus
NaDA concentration showed some upward drift (akin to that in
Figure 7). A plot of kobsd versus DME concentration
approximated first order with a slight upward curvature (Figure
9), possibly hinting at either low contributions from a highly
Figure 8. Plot of pseudo-half-order rate constants (kobsd) versus NaDA
concentration for the decomposition of THF (Scheme 1) in neat THF
at 25 °C. The curve depicts an unweighted least-squares fit to the
function f(x) = ax + b, where a = 1.5 0.2 and b = 1.57 0.07.
The [AS4]⧧ stoichiometry is consistent with an α
deprotonation via transition structure 11-α to generate
oxacarbenoid 12 as a precursor to carbene 13 (Scheme 2).35
Alternatively, a β metalation whether via a concerted E2-like
elimination or 11-β discrete carbanion 14 with post-rate-
limiting elimination to 6a is plausible. Although the isomer-
ization and consequent scrambling dissuaded us from
sophisticated isotopic labeling studies, we collected evidence
supporting the carbenoid pathway. Comparing THF to THF-d4
(15)36 afforded kH/kD ≈ 6, suggesting a rate limiting C−H(D)
cleavage at the 3 position, but it does not distinguish the two
possible mechanisms. Monitoring a mixture of NaDA, THF,
and i-Pr2ND by 1H and 2H NMR spectroscopies shows isotopic
exchange at the α protons of THF, consistent with α
deprotonation. The comparable rates of exchange and
decomposition suggest that neither metalation nor insertion
are dominantly rate limiting. The existence of discrete carbene
13, however, is not even assured.
Figure 9. Plot of kobsd versus dimethoxyethane (DME) concentration
for the decomposition of DME (eq 12) in 0.40 M NaDA at −10 °C.
The curve depicts an unweighted least-squares fit to the function f(x)
= ax, where a = 0.189 0.008.
solvent-dependent pathway or generalized medium effects. The
structure of 1f in conjunction with the idealized33 rate law (eq
15) afforded the generic mechanism in eq 16. The doubly
solvated monomer-based transition state, [A(DME)2]⧧, is
isostructural to THF-based 11 when ligand hapticity is
considered. Although DFT computations showed 16 and 17
to be computationally viable, 16 was preferred by ∼21 kcal/
NaDA in DME−toluene undergoes decomposition to give
methyl vinyl ether and sodium methoxide (eq 14). Following
the proton resonance of 1f at δ1.10 ppm shows that the decay
approximates a half-order rather than a first-order decay (akin
+
mol. The low coordination numberthe absence of a Na-
F
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(DME)3 fragment37argues against a free-ion-based mecha-
Even the smallest trialkylamines are so sterically demanding as
to afford disolvated dimers of NaDA (1a−1c) akin to those of
LDA. Compared with lithium, however, the larger sodium can
accommodate more ligands. LDA dimer, for example, never
exceeds one solvent per lithium in the solid39 or solution state21
(see 19) and is trisolvated endothermically by THF in silico.40
Even bifunctional ligands such as DME and TMEDA remain
unchelated on the LDA dimer (20).21 By contrast, NaDA in
THF forms tetrasolvated dimer 1d, and both TMEDA and
DME readily chelate dimeric NaDA (1e and 1f).6b All
substitute DMEA exothermically (see eqs 6 and 7).
nism.
−d[A2(DME)2]/dt = k[A2(DME)2]1/2[DME]1
(15)
1/2 A2(DME)2 + DME → [A(DME)2]⧧
(16)
Comments on Methods. We use a combination of tactics
to understand structure−reactivity relationships and develop
new strategies whenever possible. MCV as a method to study
aggregation, for example, has its origins in early work from
several laboratories11 and has been of enormous importance to
us for studying aggregation in systems in which M−X coupling
is not observable.8,9 To this end, our expansion of the method
to include 13C and 15N as observable nuclei is new and
noteworthy.
We also explored DOSY as a means to ascertain the structure
of NaDA using diffusion molecular weights as a proxy. DOSY is
increasingly popular,15−17 and our results could be considered
supportive. That said, however, we remain cautious owing to
significant (up to 25%) temperature-dependent changes in
measured molecular weights that do not appear to derive from
changes in structure.
Solvent Decomposition. We investigated the decom-
position of THF and DME to understand the limitations of
standard ethereal solvents as ligands for NaDA (Table 2) and
get a first peek at the mechanism of NaDA-mediated
metalations. THF decomposition occurred via tetrasolvated-
monomer-based α-elimination (11). Although isotope effects
show rate-limiting cleavage of the C−H(D) bonds at the β
position (Scheme 2), unambiguous differentiation of a carbene-
derived α-elimination (11-α) rather than E2-like β-metalation
(11-β) was elusive owing to isotopic scrambling. From a
synthetic organic (applications) perspective, the high solvent
order shows that decomposition can be suppressed by using
low ethereal ligand concentrations. Analogous rate suppression
allows LDA/THF/hydrocarbon solutions to be sold commer-
cially.
DISCUSSION
■
The first paper in this series showed that NaDA is a highly
efficacious Brønsted base when compared with LDA.7 Our
seemingly trivial but potentially consequential contribution at
the outset was to show that NaDA is soluble and stable in
DMEA and related minimally hindered trialkylamines. We
previously asserted that simple trialkylamines have been largely
overlooked as ligands for lithium salts, an oversight we attribute
to the unfortunate urge to use them in concert withrather
than to the exclusion ofstrongly coordinating ethereal
ligands.38
The structural studies described in this second paper lay
foundations for subsequent studies that will dovetail synthetic
organic applications with mechanistic investigations. We must
suppress the almost irresistible urge to rely on analogy to
lithium amides. Parallel behaviors exist, but such analogies are
imperfect and demand, at a minimum, experimental support.
Structures. A survey of NaDA reveals cyclic dimers in
solutions containing a number of standard coordinating ligands,
analogous to the dominance of LDA dimers (Scheme 3).21
Facile decomposition of DME (eq 12) proceeded via a
disolvated-monomer-based transition structure. Both 16 and 17
are computationally viable, with 16 energetically preferred. The
Scheme 3. Comparison of NaDA and LDA Structures
G
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Article
suppression of decomposition at low DME concentrations is
especially crucial if DME is to find a niche given its lability and
relatively high cost (see Table 2).
Hemilabile Trifunctional Ligands. Trifunctional PMDTA
and diglyme afford dimeric NaDA bound only as bidentate
ligands (1g and 1h). This outcome segues to a topic of long-
standing interest: hemilabile ligands.44 In contrast to transition
metal chemists attempting to build weakly chelating di- and
polyfunctional ligands that readily liberate coordination sites,45
we approach hemilability by identifying ligands that chelate
selectively in the transition state to optimize accelerations.44
Imagine, for example, transformations in which fleeting
intermediates bearing a trifunctional ligand (eq 19) are
Thoughts on Solubilities. One might argue that our
interest in the solubilities of NaDA in trialkylamines is
excessive, but applications of NaDA−R3N mixtures are
predicated on the fact that high-molarity stock solutions are
easily prepared, handled, and stored. Sodiated intermediates
must also be soluble to be of value to synthetic chemists. There
is, however, a previously undisclosed and subtle motivation for
confirming NaDA solubility: ongoing rate studies of NaDA-
mediated metalations in trialkylamines display odd rate
behaviors that we cannot reconcile easily. Such discussions
are beyond the scope of this paper but add to our obsession.
The solubility studies underscored some basic principles of
alkali metal salt solubilities that, although not unprecedented,
warrant further discussion. NaDA is highly soluble in DMEA
and DMEA−hexane yet poorly soluble in triethylamine and
TMEDA−hexane at low temperatures: why? This question is
nuanced and is summarized in eq 18.
markedly accelerated by transition-state stabilization that is
not offset by ground-state stabilization. The reader might also
realize that we have evidence to support this notion.
CONCLUSIONS
■
Dissolving unsolvated solid NaDA, denoted as (A∞)solid, to
form solubilized disolvated dimer stems largely from the
enthalpy of primary shell solvation:41,42 the ligand must bind
strongly enough to overcome the enthalpy of lattice
deaggregation. The fact that the solubility of NaDA in
trialkylamines is nearly temperature-independent shows that
the two large enthalpic contributions cancel. The overall high
solubility shows that (A2Sn)solution is favorable relative (A2Sn)solid
and (A∞)solid. Triethylamine, on the other hand, does not bind
well; the poor solubility of NaDA correlates with a small
binding constant, Ksolv(1), rather than an inherent insolubility
of A2Sn reflected in Ksolv(2). The failure of primary shell
solvation causes the insolubility of NaDA in triethylamine.
By contrast, TMEDA binds strongly: Ksolv(1) is large.
However, doubly chelated dimer 1e (A2Sn in eq 18) has
limited solubility at low temperature. Therefore, to the extent
that A2Sn (and almost every organic molecule) is more soluble
at high temperature, the solubilization of (A2Sn)solid dimer is
entropy-dominated.43 The failure of secondary shell solvation
causes the insolubility of NaDA in TMEDA−hexane.
We are enthusiastic about the promise of NaDA−DMEA
mixtures to solve metalation problems that plague synthetic
chemists. NaDA is both convenient and demonstrably effective.
It can be prepared in minutes using standard glassware and
stored for months with refrigeration as 1.0 M DMEA solutions.
Metalation rates are typically orders of magnitude higher than
those for LDA−THF.7 The obvious limitations include the
higher costs and unpleasant odors of trialkylamines, but neither
precludes application to difficult metalations. Another point
that should not be overlooked is that DMEA is substitutionally
labile. Stronger ligands, even potentially expensive ligands, can
be added before the metalation to accelerate itthey door
after the metalation to modulate the reactivity of the resulting
sodiated intermediate. Furthermore, quite unlike LDA, NaDA
shows little tendency to form mixed aggregates.21 We are
encouraged by the well-defined aggregation and solvation states
described herein that are required to unravel mechanistic details
of NaDA-mediated metalations and correlate them with
selectivities.
Synthetic Implications. In our first contribution,7 we
emphasized the merits of NaDA−DMEA for metalations owing
to its ease of handling and resistance to base-mediated solvent
decomposition.30,31 However, the substitutional lability of
trialkylamines is also synthetically important. In forthcoming
papers, we will explore the effects of ethereal ligands on
reactivities of NaDA−DMEA mixtures. Ongoing studies show
that THF elicits large accelerations relative to that of NaDA−
DMEA while the metalation rate far exceeds the THF
decomposition rate. The short half-life of NaDA in ethereal
stock solutions by no means precludes their use as additives.
Mono- and difunctional ethers readily displace coordinated
DMEA in NaDA−DMEA stock solutions. Moreover, when
robust trialkylamines are required to force a recalcitrant
metalation, the resulting saltsarylsodiums, for example
can be treated with ethereal ligands after the metalation to
modulate their reactivities. Again, the ligand substitution will be
highly favorable.
EXPERIMENTAL SECTION
■
Reagents and solvents. THF, DME, diethyl ether, TMEDA,
PMDTA, diglyme, hexane, and all trialkylamines were distilled from
blue or purple solutions containing sodium benzophenone ketyl.
[15N]diisopropylamine,46 [15N]dicyclohexylamine,47 and [15N]-
isopropylcyclohexylamine48 have been described previously. NaDA
was prepared from diisopropylamine, isoprene, DMEA, and sodium
dispersion using a modified7 procedure first reported by Wakefield.5b
A precautionary crystallization was used for the work described herein.
Solutions of NaDA were titrated using a literature method.49 NaICA
was prepared with an optimized dissolving-metal-based preparation
analogous to that used to prepare NaDA.7,9a
NaDCA. NaDCA is more conveniently prepared using n-
butylsodium50 rather than sodium dispersion because of its lower
solubility. To a dry 15 mL pear flask charged with n-butylsodium (33.0
mg, 0.413 mmol) was added DMEA (3.3 mL) at room temperature.
On complete dissolution of the n-butylsodium, neat dicyclohexylamine
(66.0 μL, 0.33 mmol) was added to provide a stock solution. 13C
H
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Article
NMR spectrum (125.72 MHz, DMEA) δ 61.9, 41.6, 27.3, 26.7; 15N
NMR spectrum (50.66 MHz, DMEA) 86.9.
(8) (a) Renny, J. S.; Tomasevich, L. L.; Tallmadge, E. H.; Collum, D.
B. Angew. Chem., Int. Ed. 2013, 52, 11998. (b) Weingarten, H.; Van
Wazer, J. R. J. Am. Chem. Soc. 1965, 87, 724. (c) Goralski, P.; Legoff,
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Gruver, J. M.; Collum, D. B. J. Am. Chem. Soc. 2008, 130, 4859.
NMR Spectroscopic Analyses. NMR samples for reaction
monitoring were routinely prepared using stock solutions of NaDA
and sealed under partial vacuum. DMEA-free solutions of NaDA with
added ligands used DMEA-free crystallized NaDA. Samples were
routinely flame-sealed except when used in experiments involving
1
serial titration with a coordinating ligand. Standard H, 13C, and 15N
spectra were recorded on a 500 MHz spectrometer at 500, 125.79, and
50.66 MHz, respectively. The 13C and 15N resonances were referenced
to the CH2O resonance of THF at −90 °C (67.57 ppm) and neat
Me2NEt at −90 °C (25.7 ppm), respectively.
(10) Barton
Commun. 1982, 47, 594.
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solvation (including lithium and sodium solvated by THF and DME),
see: Ziegler, M. J.; Madura, J. D. J. Solution Chem. 2011, 40, 1383.
(14) Measuring the mole fraction within only the ensemble of
interest rather than the overall mole fraction of NaDA added to the
samples eliminates the distorting effects of impurities.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b03061.
■
S
Structural, kinetic, and computational data; complete ref
12 (PDF)
(15) (a) Li, D.; Keresztes, I.; Hopson, R.; Williard, P. G. Acc. Chem.
Res. 2009, 42, 270. (b) Kagan, G.; Li, L.; Hopson, R.; Williard, P. G.
Org. Lett. 2010, 12, 520. (c) Su, S.; Hopson, R.; Williard, P. G. J. Org.
Chem. 2013, 78, 11733. (d) Guang, J.; Hopson, R.; Williard, P. G. J.
Org. Chem. 2015, 80, 9102. (e) Guang, J.; Liu, Q. P.; Hopson, R.;
Williard, P. G. J. Am. Chem. Soc. 2015, 137, 7347. (f) Su, G.; Guang, J.;
Li, W.; Wu, K.; Hopson, R.; Williard, P. G. J. Am. Chem. Soc. 2014,
136, 11735.
AUTHOR INFORMATION
Corresponding Author
*dbc6@cornell.edu
ORCID
David B. Collum: 0000-0001-6065-1655
Notes
■
(16) (a) Armstrong, D. R.; Harris, C. M. M.; Kennedy, A. R.; Liggat,
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Institutes of Health (GM039764) for
support. This work made use of the Cornell NMR Facility,
which is supported in part by the NSF-MRI Grant CHE-
1531632.
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(1−n) 1/(1−n)
[substrate] = {(n − 1)kobsdt + [substrate]0
}
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DOI: 10.1021/jacs.7b03061
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