Reactions of Sodium Diisopropylamide: Liquid-Phase and Solid-Liquid Phase-Transfer Catalysis by N, N, N′, N″, N″-Pentamethyldiethylenetriamine

Article abstract of DOI:10.1021/jacs.1c06528

Sodium diisopropylamide (NaDA) in N,N-dimethylethylamine (DMEA) and DMEA-hydrocarbon mixtures with added N,N,N′,N″,N″-pentamethyldiethylenetriamine (PMDTA) reacts with alkyl halides, epoxides, hydrazones, arenes, alkenes, and allyl ethers. Comparisons of PMDTA with N,N,N′,N′-tetramethylethylenediamine (TMEDA) accompanied by detailed rate and computational studies reveal the importance of the trifunctionality and κ2-κ3 hemilability. Rate studies show exclusively monomer-based reactions of 2-bromooctane, cyclooctene oxide, and dimethylresorcinol. Catalysis with 10 mol % PMDTA shows up to >30-fold accelerations (kcat > 300) with no evidence of inhibition over 10 turnovers. Solid-liquid phase-transfer catalysis (SLPTC) is explored as a means to optimize the catalysis as well as explore the merits of heterogeneous reaction conditions.

Full text of DOI:10.1021/jacs.1c06528

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Article
Reactions of Sodium Diisopropylamide: Liquid-Phase and Solid−
Liquid Phase-Transfer Catalysis by
N,N,N′,N″,N″‑Pentamethyldiethylenetriamine
Yun Ma, Ryan A. Woltornist, Russell F. Algera, and David B. Collum*
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ABSTRACT: Sodium diisopropylamide (NaDA) in N,N-dime-
thylethylamine (DMEA) and DMEA−hydrocarbon mixtures with
added N,N,N′,N″,N″-pentamethyldiethylenetriamine (PMDTA)
reacts with alkyl halides, epoxides, hydrazones, arenes, alkenes,
and allyl ethers. Comparisons of PMDTA with N,N,N′,N′-
tetramethylethylenediamine (TMEDA) accompanied by detailed
rate and computational studies reveal the importance of the
trifunctionality and κ2−κ3 hemilability. Rate studies show exclusively monomer-based reactions of 2-bromooctane, cyclooctene
oxide, and dimethylresorcinol. Catalysis with 10 mol % PMDTA shows up to >30-fold accelerations (kcat > 300) with no evidence of
inhibition over 10 turnovers. Solid−liquid phase-transfer catalysis (SLPTC) is explored as a means to optimize the catalysis as well as
explore the merits of heterogeneous reaction conditions.
hexane mixtures.7,12 We did this to maximize comparisons with
INTRODUCTION
■
the wealth of data accrued on LDA in THF.18 THF is an
Despite occasional bursts of activity through the last
century,1−6 organosodium chemistry has not kept abreast
adequate solvent for NaDA, but the half-life to base-mediated
destruction (t1/2 = 1.0 h at 25 °C)12b,19 restricts its use for
recalcitrant metalations that could most benefit from NaDA’s
high reactivity.7,12 NaDA solvated by N,N,N′,N′-tetramethyle-
thylenediamine (TMEDA) shown crystallographically to be
dimer 4 by Andrews and co-workers5b represented an
important milestone toward rendering NaDA more conven-
ient, but it remained unnoticed by the synthetic organic
chemistry community. NaDA can also be prepared as 1.0 M
stock solutions that are stable for months with refrigeration
using simple trialkylamines such as N,N-dimethylethylamine
(DMEA), N,N-diethylmethylamine (DEMA), N,N-dimethyl-
butylamine, and N-methylpyrrolidine.7,12b,20 Moreover, these
weakly coordinating trialkylamines are substitutionally labile to
standard ethereal ligands such as THF.12b,21
with organolithium chemistry by any measure.6,7 The most
reactive reagents such as sodium diisopropylamide (NaDA)
and n-butylsodium that would logically be cornerstones of the
discipline suffer from low solubility in inert hydrocarbon
solvents and instability in ethereal solvents if not handled
correctly.8 These were solvable problems, and serious progress
toward developing convenient, highly reactive bases has been
made.4,5,8−13 Given the lackluster interest from synthetic
chemists, it follows that organosodium chemistry has received
even less attention from those who care about structure and
mechanism. Representation of organosodiums in the crystallo-
graphic literature is adequate,14 but spectroscopic,15 mecha-
nistic,16 and even computational studies are sparse.17
Our efforts to foster new applications of organosodium
chemistry have relied on understanding structure−reactivity
principles of NaDA.12 In this paper, we describe a search for a
robust ligand that can catalyze NaDA-mediated metalations
(eq 1), a plan that brought several seemingly disparate issues
into focus.
Crystallographically focused groups such as those of Mulvey
and Andrews long ago noticed the merits of polyamines such
as N,N,N′,N′,N″-pentamethyldiethylenetriamine
(PMDTA).6b,22 We suspected that such polyamines would
also elicit high reactivities with highly manageable (limited)
decomposition.12b,19,23 We had examined the structures of a
number of NaDA solvates.12b Studies of reactivity described in
i‐Pr2NNa
substrate ⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯→ product
catalytic ligand
(1)
Received: June 23, 2021
Published: August 10, 2021
Robust Solvents. There is little reason to believe that
solvents (ligands) optimized for organolithium chemistry
should be optimal for organosodium chemistry as well. Much
like other practitioners of organoalkali metal chemistry,
however, we have not resisted the siren call to use THF; all
of our rate and mechanistic studies to date have used THF/
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this paper are founded on solution structural studies of amine-
solvated dimers 1−5.
Solid−Liquid Phase-Transfer Catalysis (SLPTC). If one
can solve the aforementioned problems and achieve accel-
eration and catalysis, any stereo- or regiocontrol necessarily
relies on the suppression of the uncatalyzed background
reaction. This could be acutely challenging for reactive
organosodium-based reagents. We have accrued ample
evidence that NaDA in simple trialkylamines displays muted
basal reactivities at least relative to THF. A complementary
approach, however, would be to exploit a two-phase system in
which NaDA is an insoluble solid suspended in a hydrocarbon
(eq 6). The catalytically active ligand assumes the role of
phase-transfer catalyst and, ideally, isolates the reaction to the
solution phase containing only ligated reagent.
Hemilability. In a 1992 review, we challenged a number of
misconceptions about the chelate effect in general and
TMEDA in particular.24 For example, despite TMEDA’s
reputation for eliciting marked accelerations in organolithium
chemistry owing to its putative prowess as a chelating ligand
a prowess we claimed was overstated and poorly understood
stabilization of a rate-limiting transition structure by chelation
will be partially, if not entirely, offset by chelation in the
reactant (6, eq 2). By contrast, if the reactant is not chelated
(see 7), then the full advantages of chelation exclusively in the
transition state should maximize the putative benefits of the
chelate effect.25 This little-used variant of “hemilability”most
users focus on labile chelateselicited up to 104-fold
accelerations for LDA-mediated metalations.26,27 Could the
larger sodium ion support an analogous κ2−κ3 hemilabile
relationship (eq 3) using PMDTA-solvated dimer 5?
ligand catalysis
R−Nasolid + E−X ⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯→ R−E + NaXsolid
(6)
Whereas liquid−liquid phase-transfer catalysis (LLPTC)
enjoys considerable notoriety,31 solid−liquid phase-transfer
catalysis (SLPTC) is a much smaller niche.31b,32,33 Examples of
SLPTC are largely proof-of-principle or commodity chemical
applications on simple systems.32 Binaphthyl-based phosphate-
catalyzed reactions reported by Toste and co-workers are
emblematic of a few standout exceptions.34−36 Like any
heterogeneous reaction, however, complexity can rear its ugly
head. Substrates with standard functionalities can solubilize the
reagent or cause a reaction to occur on the solid surface at the
so-called “omega phase”.32 Further challenges stemming from
the heterogeneity include complex reaction orders, occlusion
of the insoluble reagent by precipitation of the product,37 and
dependencies on particle size, stir rates, and ultrasound
agitation.36a,38,39 Complexities aside, the importance of under-
standing the molecular and mechanistic principles underlying
SLPTC is enormous given that any heterogeneous reaction is
implicitly subject to the vicissitudes of SLPTC, and slurries are
commonplace inside pharmaceutical process laboratories and
production facilities.40 Why leave studies of these systems to
the chemical engineers?
In this paper, we examine the reactivity of NaDA focusing
on PMDTA.6a,22 Both TMEDA and PMDTA facilitate
metalations, but PMDTA is far superior, eliciting up to >102-
fold accelerations attributable to hemilability. Catalysis is
optimal when NaBr or NaCl precipitate, but turnover is
observed even for reactions affording soluble sodium salts.
SLPTC is explored as a means to amplify the relative
importance of catalysis by suppressing the basal rates. The
protocols described herein provide a foundationthe
previously derided proof-of-principle experimentfor catalysis
that may find concrete applications.
Ligand-Based Catalysis. Imagine the idealized ligand
displaying the generality of BINAP [(2,2′-bis-
(diphenylphosphino)-1,1′-binaphthyl)] that could be used
catalytically to modify a wide range of inherently stoichiometric
organolithium reactions. It would be transformational.
Unfortunately, there are few examples of such ligand-based
catalysis in organolithium chemistry.28−30 We suspect that the
high affinities of polydentate ligands for soluble and relatively
unhindered lithium salt products such as LiCl (eq 4) sequester
ligand and preclude turnovers. Notably, a large proportion of
the examples involve additions to imines to form lithium
dialkylamides, which, by virtue of their high steric demands,
release the ligands.28−30 We surmised that the insolubility of
inorganic sodium salts such as NaCl or NaBr would foster
turnover (eq 5) and further held an altogether unsupported
hope that the sodium ion might release the ligand even from
soluble sodium salts.
RESULTS AND DISCUSSION
■
Core observations are summarized in Table 1. Although NaDA
can be prepared as a 1.0 M solution in DMEA in a few
minutes,12 we take the added precaution of using NaDA
isolated as a white solid because of our emphasis on rate
studies. Han and co-workers have provided a direct
preparation of NaDA/PMDTA in situ.13 Reaction rates for
the metalations depicted generically in eq 7 were monitored by
in situ IR41 or H NMR spectroscopies or by gas chromato-
1
graphic analyses of quenched samples. Because of product
volatilities, the yields are determined relative to internal
standards unless explicitly stated otherwise. The relative rate
constants (krel) for homogeneous reactions are measured at
constant NaDA and substrate concentration (0.12 M each)
ligand
R−Li + E−X ⎯⎯⎯⎯→⎯ R−E + (ligand)LiX
(4)
ligand
R−Na + E−X ⎯⎯⎯⎯→⎯ R−E + NaXsolid + ligand
(5)
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PMDTA owing to concentration dependencies delineated
below. Moreover, rather than cluttering Table 1 with
additional comparisons, we simply note that metalations
using 1.0 equiv of PMDTA proceed at rates comparable to
analogous reactions in neat THF described previously.12,43
Large differences between TMEDA and PMDTA confirm the
importance of hemilability.
Table 1. PMDTA-Dependent Relative Rate Constants (eq
8) for NaDA-Mediated Metalations (eq 7)
krel = (kDMEA + kPMDTA/10)/kDMEA
(8)
Although many of the reactions in Table 1 are self-
explanatory, some require additional comment. The elimi-
nation of 1-fluorooctane (entry 3) fails in THF owing to THF
decomposition, illustrating the advantages of a robust
ligand.12e The accompanying isomerization of the resulting
terminal alkene studied previously for NaDA/THF,12c
however, is unavoidable under the forcing conditions. The
9:1 regioselectivity for the elimination of 2-bromooctane to
form 1-octene (entry 4) is lower than the >30:1 selectivity
observed in THF,12e which is the highest reported to date for
such a base-mediated elimination of 11.44 The relative rates for
axial and equatorial eliminations (entries 5 and 6) are
surprisingly similar (kax/keq ≈ 10 adjusted for the temperature
differential). This was also observed for NaDA/THF and
traced to E2-like axial elimination of 12 and carbene-based
equatorial elimination of 13.12e
The contrasting stereocontrol in cis and trans epoxides in
entries 11 and 12 is precedented for other bases.45,46 Only a
few base-mediated eliminations of the trans isomer in entry 11
are reported,46 presumably stemming, in part, from an aversion
to reporting poor selectivities. Terminal epoxides (not shown)
lead to oligomerization to form polyethers. Entries 16−18
reveal little acceleration by PMDTA, which could arise from
high basal reactivities of the uncatalyzed reaction or because
the tridentate ligand suppresses requisite substrate coordina-
tion to sodium at the transition state. The metalation in eq 9
illustrates a regioselectivity that had been studied using NaDA/
THF.12e We thought that PMDTA might suppress a facile
equilibration with an alternative regioisomer ortho to the
chloro, but the selectivity suggests that equilibration inter-
vened.
Some arenes undergo partial orthometalation, displaying soft
equilibria with both unmetalated and metalated forms
coexisting (eq 10). We hoped that PMDTA might improve
such a balanced equilibrium observed with both NaDA/
THF12d and LDA/THF47 by selectively binding to the aryl
sodium, but a soft equilibrium was observed yet again. Rate
studies akin to those described below reveal a monomer-based
metalation (Supporting Information).
with 10 mol % PMDTA. Catalysis was confirmed when
following reactions using 10 mol % PMDTA to full conversion
showed neither loss in efficacy nor significant deviation from
upwardly curving decays (vide infra). The reported values of
kPMDTA are gleaned from initial rates referenced to the basal
(uncatalyzed) rates according to eq 8. The divisor of 10 in eq 8
accounts for the 10 mol % of catalyst. The basal rates using the
less hindered N,N-diethylmethylamine (DEMA) as the solvent
typically fall in the range of 2-fold slower to 3-fold faster than
for DMEA,42 suggesting that DEMA could be used to amplify
the relative impact of catalysis in select cases.
Accelerations using 100 mol % (>1.0 equiv) PMDTA are 3−
6-fold (rather than 10-fold) higher when compared with 10%
Acceleration and Catalysis. Acceleration and turnover
(catalysis) are described using several cases emblematically.
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Dehydrohalogenation of 9 (Table 1, entry 1) with equimolar
NaDA in DMEA is slow at −30 °C (Figure 1). After
not emerge concurrently); no such inhibition at 50%
conversion is observed. The elimination of epoxide 15 plays
a central role during investigations of SLPTC (vide infra).
We examined tetramines 25 and 26 to ascertain if
tetradentate binding might be superior.50 Muted rates relative
to PMDTA suggest that three-coordinate binding is preferred
and that the added steric demands are detrimental. Various
polyethers were avoided assiduously owing to facile decom-
position.12b
Mechanisms: General. Rate studies were carried out using
the method of initial rates51−53 and monitored using either 1H
NMR spectroscopy or GC analysis of quenched aliquots.54 All
transition structures were examined using density functional
theory (DFT) computations55 carried out at the M06-2X level
of theory.56−58 (The computations described herein are
archived in the Supporting Information.)
The solvent substitution in eq 11 (A = NaDA subunit; S =
DMEA; L = TMEDA or PMDTA) illustrates the structural
foundations underlying the rates.12b It would be possible but
foolhardy to attempt to understand the basic principles of
NaDA-mediated metalations under conditions in which the
structure of NaDA is shifting from A2S2 to A2LS to A2L2. We
ring-fenced the complexity by carrying out the bulk of the rate
studies at low DMEA concentrations and high TMEDA or
PMDTA concentrations, which strongly favor A2L2. A high
enthalpic preference for A2L2 relative to A2S2 at reduced
temperatures further promotes its formation. Although we
avoid conditions favoring A2LS for the detailed rate studies,
A2LS is mechanistically important under conditions of catalysis
(vide infra).
Figure 1. Metalation of 0.10 M 9 with 0.12 M NaDA in neat DMEA
at −30 °C monitored by 1H NMR spectroscopy. PMDTA (0.010 M,
0.10 equiv) was injected (see arrow).
establishing a basal rate, 10 mol % (per sodium) PMDTA is
injected (see arrow). Precipitation of NaBr is an excellent
visual cue that the reaction has commenced. The accelerated
metalation proceeds to completion through the requisite 10
turnovers with no noticeable stalling. 1-Octene is formed in
1
82% H NMR yield relative to an internal benzene standard.
No N-alkylation (<5%) occurs for the NaDA/THF variant12c
1
as evidenced by H NMR spectroscopy and GC-MS with
comparison to a sample of (i-Pr)2NC8H17. By contrast,
catalytic TMEDA shows no detectable acceleration, which is
consistent with recent studies of NaHMDS showing that
TMEDA is a mediocre chelating ligand.48
Elimination of epoxide 15 (Table 1, entry 10) by 1.2 equiv
of NaDA followed by 10 mol % PMDTA shows catalysis with
attenuated acceleration (Figure 2). Notably, the product
K1
K2
A2S2 + 2L F A2SL + L + S HoI A2L2 + 2S
(11)
Mechanism of Cyclooctene Oxide Elimination. Mech-
anistic principles common to all of the metalations are
illustrated with the metalation of cyclooctene oxide (eq 12).
A plot of initial rates versus PMDTA concentration (Figure 3)
shows that the metalation rate saturates at low DMEA
concentrations (curve a) resulting from the full conversion of
A2S2 to A2L2. The observed rate at full saturation is
indistinguishable from that observed in the absence of
DMEA, conditions in which A2L2 is shown spectroscopically
to form quantitatively.12b In neat DMEA, by contrast,
saturation is not achieved (curve b); mixed solvate A2LS
remains dominant. Figure 3 is a reminder of a recurring theme
of the probative power of kinetics to study solvation as a
molecular phenomenon.
Figure 2. Metalation of 0.010 M cyclooctene oxide (15) with 0.12 M
NaDA in 1.0 M DMEA at 25 °C monitored by 1H NMR
spectroscopy. PMDTA (0.10 equiv, 10 mol %) was injected (arrow).
alkoxide does not precipitate from solution, yet there is no
evidence of autoinhibition. If, for example, PMDTA was
binding appreciably but reversibly to the alkoxide in a 1:1
stoichiometry, one would expect a burst of reaction to 10%
conversion followed by a return to the basal rate. Such biphasic
kinetics are not observed. Similarly, autoinhibition owing to
the formation of an unreactive i-Pr2NNa−RONa mixed
dimer6a,49 could have caused slowing or stalling at 50%
conversion (provided a mixed-aggregate-based metalation does
Under conditions favoring full saturation, metalation of 15
displays a half-order NaDA dependence (Figure 4). The
saturation kinetics and the NaDA order are described by the
generalized and idealized59 rate law in eq 13 and mechanism in
eqs 15−17. At saturation, the rate law reduces to eq 14 and the
mechanism to eqs 16 and 17.
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have kept the Noyes equation in the shadows,12b,61 all afforded
1.0 < n < 2.0.
[E] = ((n − 1)kobsd + [E0]−(n−1) −1/n−1
)
(18)
Under conditions of ligand-catalyzed metalations (10 mol %
PMDTA), the metalations would likely proceed via the same
monomer-based transition structure, but the low L concen-
tration with excess A2S2 imposes the formation of A2LS (eq
11), a preference that is enhanced by correlated solvation (K1
> K2).12b,62,63 The same monomer-based metalation originat-
ing from a different ground state results in quite different
concentration dependencies as described by eqs 19−21. The
rate law predicts a zeroth-order DMEA dependence and an
inverse-half-order dependence on NaDA. (Such a fractional-
order inhibition by NaDA was observed for 1-pentene
isomerization as illustrated in Figure 5.) It suggests that
Figure 3. Plot of initial rates versus [PMDTA] in 1.0 M DMEA in
hexanes cosolvent for the elimination of cyclooctene oxide (0.067 M)
in the presence of 0.10 M NaDA at 25 °C. Curves depict unweighted
least-squares fits to y = ax/(1 + bx). Curve a (1.0 M DMEA/toluene):
a = (3.5 0.9) × 104; b = (1.9 0.6) × 104. Curve b (neat DMEA):
a = (2.0 0.2) × 103; b = (1.7 0.4) × 103.
Figure 5. Plot of initial rate versus [NaDA] in DMEA for the
isomerization of 1-pentene (0.050 M) in the presence of 10%
PMDTA at 25 °C. The curve depicts an unweighted least-squares fit
to y = axn + c (a = (2.3 1.0) × 105, c = (1.9 0.4), n = (−0.48
0.11).
Figure 4. Plot of initial rate versus [NaDA] in 1.0 M DMEA in
hexane cosolvent for the elimination of cyclooctene oxide (0.067 M)
in the presence of 2.0 M PMDTA at 25 °C. The curve depicts an
unweighted least-squares fit to y = k[NaDA]n: k = (4.6 0.7) × 103;
n = 0.5 0.1.
suppressing the NaDA concentration by slow addition would
amplify the relative influence of catalysis, krel, in eq 8.
Promotion of catalysis and suppression of the basal rate,
−d[E+]/dt = k[E+][A2(total) 1/2[L]/(1 + k′[L]) + c
]
(13)
(14)
k
DMEA, by lowering the concentration of A2S2 should maximize
the influence of catalysis on selectivity.
−d[E+]/dt = k[E+][A2L2]1/2
K3
A2SL F 1/2A2S2 + AL
(19)
K′
1/2A2S2 + L F 1/2A2L2 + S
(2)
(4 or 5)
(15)
k′
AL + E+ → [ALE+]‡
(20)
(21)
K″
1/2A2L2 HoI AL
(27)
rate ∝ [A2LS]1[A2S2]−1/2[S]0
(4 or 5)
(16)
(17)
k
AL + E+ → [ALE+]‡
Deuterated epoxide 15-d2 (eq 22) held promise to
demonstrate both the expected kinetic isotope effect on the
elimination as well as ruling out carbenoid-based mechanisms.
Unfortunately, we observed significant washing out of the
deuteriums in the products and recovered epoxide, suggesting
a reversible metalation (eq 23). Although it appeared as
though the elimination per se occurs via a 1,2-elimination, the
exchange undermined the experiment, while the source of the
protons remained elusive.64
(27)
(28)
The half-order in NaDA and first-order in substrate suggest
that reactions under standard synthetic conditions using
equimolar NaDA and substrate ([E] = [Atotal]) should be
1.5-order overall. As a largely academic exercise, metalation of
15 and several other substrates were fitted to the nonlinear
Noyes equation (eq 18)60 to determine the overall reaction
order, n, by best fit. Although the inherently large error bars
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The accelerations by PMDTA when compared with
TMEDA attest to the hemilability (eq 24). The computed
transition structure depicted generically as [ALE+]‡ in eq 17 is
shown as 29 in Figure 6.
Figure 7. Plot of initial rates versus [TMEDA] in 1.0 M DMEA in
hexanes cosolvent for the elimination of cyclooctene oxide (0.067 M)
in the presence of 0.10 M NaDA at 25 °C. Curves depict unweighted
least-squares fits to y = ax/(1 + bx) + c: a = (1.7 0.9) × 105; b =
(1.4 0.8) × 105; c = 0.53 (set by measurement).
Figure 8. Computed transition structures for the elimination of 1-
bromooctane by NaDA/PMDTA (31) and NaDA/TMEDA (32).
Figure 6. Computed monomer-based transition structures for the
elimination of cyclooctene oxide by NaDA/PMDTA (29) and
NaDA/TMEDA (30).
Because of the central importance of TMEDA in organic
chemistry, we determined the TMEDA dependence for the
elimination of cyclooctene oxide in TMEDA/DMEA and
observed saturation kinetics with a 2-fold acceleration off the
basal rate (Figure 7). The concentration of TMEDA in which
saturation is attained attests to a similar binding constant as
PMDTA. Transition structure 30 of stoichiometry [ALE+]‡ is
shown in Figure 6.
Mechanisms of Dehydrohalogenations. Analogous rate
studies for the PMDTA-mediated elimination of 1-bromoctane
(Table 1, entry 1) afford rate data consistent with eqs 13−17.
Monitoring 2,2-d2-9 (eq 25) shows an isotopic distribution and
isotope effect that confirms a standard vicinal elimination such
as the anti elimination via transition structure 31 (Figure 8).65
The analogous syn elimination via 32 displaying a distinct Na−
Br contact was not experimentally excluded but is calculated to
be of comparable stability to 31. Although not studied
thoroughly, the isotopically labeled chloro analogue (eq 26)
shows an isotope effect and product distribution consistent
with a carbenoid mechanism studied previously using NaDA/
THF.12e
Solid−Liquid Phase-Transfer Catalysis. Attempts to
reduce the basal reactivity using triethylamine afforded
marginal solubility, prompting us to consider using suspensions
of NaDA in hydrocarbons and employing the polyamines as
phase-transfer catalysts. Dehydrobromination of 1-bromooc-
tane (9) by a suspension of NaDA at −15 °C revealed a barely
measurable basal reaction (Figure 9). Addition of 10 mol %
PMDTA elicits a 40-fold acceleration with full conversion
attesting to 10 turnovers. The solid-to-solid conversion
without stalling shows that occlusion of the NaDA by
deposited NaBr is not a problem.37 Moreover, the upward
curvature is consistent with a constant (steady-state)
concentration of NaDA−PMDTA66 superimposed on a first-
order dependence of 9. (Titrations of solid NaDA in hexane
with PMDTA or TMEDA formed A2L2 (4 or 5) linearly
proportional to added “L” with no evidence of partial solvate
A2L.)12b A plot of initial rates versus PMDTA concentration is
akin to a plot versus A2L2 concentration and reveals an order
on the high side of a half-order (Figure 10). The mechanism is
described by eqs 27−29 with transition structure 31 (Figure 8)
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could reflect the solubility limit of NaDA solvated by epoxide
15, we suspect that soluble mixed aggregates are involved.69
Most importantly, the distribution of Z-16 and (E-16 + 39)
(an unresolved nearly 1:1 mixture) serves as a fingerprint of
the polyamine-free elimination, offering an independent
measure of the relative contributions of uncatalyzed and
catalyzed elimination that complements that derived from
ligand-dependent metalation rates. Table 2 illustrates the
product distribution measured vs PMDTA concentration.
Figure 9. Metalation of 0.15 M 9 with solid NaDA (equiv of 0.16 M)
suspended in hexane at −15 °C monitored by GC analysis of
quenched aliquots. PMDTA (0.016 M, 0.10 equiv) was injected (see
arrow).
Table 2. Product Ratios for the Elimination of Cyclooctene
Oxide with NaDA in Hexane in the Presence of PMDTA
PMDTA (mol %)
(Z-16+E-16):39
0
5
0.7
7
10
5
100
12
14
50
a
a
Slow addition over 9 h with a syringe pump.
Taken together, minimizing the epoxide concentration
should minimize the basal rate relative to the catalyzed rate.
To test this hypothesis, we dropped the catalyst loading to 5
mol %, which affords a particularly poor selectivity consistent
with a high relative basal rate (Table 2). Rapid addition affords
a 7:1 selectivity consistent with the basal and catalyzed rates
near parity. Slow addition by motor-driven syringe over 9 h
reveals a measurably improved 14:1 relative rate of the
catalyzed elimination (Table 2). Thus, using SLPTC to
catalyze a reaction in which the substrate can mediate its
own metalation will witness significant substrate concentration
dependencies. Most substrates have ligating functionality; one
could imagine high coordination numbers in the substrate-
mediated substrate metalations in organosodium chemistry.
Figure 10. Plot of initial rates versus [PMDTA] in hexanes for the
elimination of bromooctane 9 (0.050 M) in the presence of 0.10 M
NaDA at −40 °C. The curve depicts an unweighted least-squares fit to
y = axn: a = (1.7 0.03) × 102; n = 0.65 0.08.
shown in the rate studies above. Similar results for SLPTC
using TMEDA are observed but with muted accelerations as
noted above.
−d[E+]/dt = k[E+][A2L2]1/2
(27)
Keq
An(solid) + L HooI A2L2
(28)
(29)
(5)
CONCLUSIONS
■
k
The work described above covers considerable intellectual
territory and is a lot to digest. Those interested in
crystallography have certainly noticed the merits of PMDTA
as a trifunctional ligand for sodium.6b,22 Its capacity to serve as
a base-resistant, highly efficacious surrogate for THF leads us
to suspect that PMDTA may play a central role if
organosodium chemistry pushes its way into more mainstream
applications.
1/2A2L2 + E+ → [ALE+]‡
SLPTC of epoxide elimination is challenging and under-
scores a potential limitation of the strategy because epoxides
also function as ethereal ligands and can mediate phase
transfer, imposing elevated basal rates.67 Cyclooctene oxide
offers a particularly interesting view owing to differential
selectivities with and without catalysis (eq 30). In the absence
of added ligand, NaDA-mediated metalation of 15 in hexane
affords a mixture of cis cyclooctenol Z-16, trans cyclooctenol E-
16, and carbene-derived alcohol 39. Alcohols Z-16 and E-16
are observed in NaDA/DMEA-mediated elimination.12a
Alcohols Z-16 and 39 are formed in lithium amide-mediated
eliminations.68 Moreover, the reaction becomes homogeneous
at approximately 50% conversion. Although, in principle, this
The importance of hemilability, which relies on elevated
coordination numbers in the rate-limiting transition structures
relative to the reactants, is also a promising construct. To
foreshadow hemilability in other NaDA-mediated reactions,
one could start by measuring the efficacies (rates) of PMDTA
versus TMEDA. We are reminded once again that rate studies
are a particularly powerful means of studying metal ion
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Article
mg, 1.62 mmol) under an argon atmosphere at 25 °C was added
epoxide 15 (189 mg, 1.50 mmol) in hexane (4.0 mL). The reaction
mixture was stirred for 1.2 h, quenched by the addition of saturated
NH4Cl solution (4 mL), and extracted with ether (3 × 8.0 mL). The
organic layer was washed with brine (8 mL) and dried over Na2SO4.
Evaporation of solvent followed by flash chromatography of the
resulting crude residue using hexane/ether (5/1) as eluent afforded
an E/Z mixture of Z-16 (138 mg, 73% yield) and E-16 (34 mg, 18%
yield) displaying spectroscopic data consistent with literature values.72
solvation by capturing the fleeting solvation events beyond the
view of the various spectroscopies.
It would be premature to declare that organosodium
chemistry will be catapulted forward by the benefits of
ligand-based catalysis in a broad sense, but catalysis of
NaDA-mediated metalations is encouraging. Let us consider
alkylations of seemingly related sodiated imines or hydrazones
(eq 31), which have been alkylated enantioselectively as the
lithium salt using stoichiometric sparteine by McClacken and
co-workers.70 It does not take a particularly fertile mind to
imagine how chiral PMDTA analogues might impart
enantioselectivity and do so catalytically. Of course, there
remain significant hurdles to overcome before credible
applications of catalyzed organosodium chemistry emerge.
We are not well-positioned to do this justice; crowdsourcing
this to the free market of ideas where specific needs drive the
solutions is more appropriate anyway.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c06528.
■
sı
Spectral, rate, and computational data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
David B. Collum − Department of Chemistry and Chemical
Biology, Baker Laboratory, Cornell University, Ithaca, New
York 14853−1301, United States; orcid.org/0000-0001-
6065-1655; Email: dbc6@cornell.edu
During efforts to maximize the relative influence of catalyzed
metalations, we turned to SLPTC to optimize potentially
beneficial stereo-, regio-, or chemoselectivities imparted by
catalysis. As above, it is a minor extrapolation to imagine using
SLPTC on other hexane-insoluble organosodium or even
organolithium reagents. Thinking more generally, we wonder if
instead of focusing on catalytically active discrete organo-
transition catalysts one might focus on stoichiometric reactions
of inexpensive first-row transition metals that could be
catalyzed by designer ligands. Once again, we leave this
thought for others to ponder.
Authors
Yun Ma − Department of Chemistry and Chemical Biology,
Baker Laboratory, Cornell University, Ithaca, New York
14853−1301, United States
Ryan A. Woltornist − Department of Chemistry and Chemical
Biology, Baker Laboratory, Cornell University, Ithaca, New
York 14853−1301, United States
Russell F. Algera − Department of Chemistry and Chemical
Biology, Baker Laboratory, Cornell University, Ithaca, New
York 14853−1301, United States
SLPTC is already a very broad topic in that suspensions are
commonplace in pharmaceutical process laboratories and
plants. The functional molarity of a heterogeneous reac-
tionthe moles per liter within a vatis constrained by the
quantity and physical properties of the insoluble reagent and
the size of the paddle. Although the engineers are particularly
good at solving such technical problemsthey have very big
paddleswe wonder if the solid−liquid phase-transfer
problems inherent to heterogeneous reactions might benefit
from additional molecular-level scrutiny.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c06528
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the National Institutes of Health (GM131713) for
support.
■
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NOTE ADDED AFTER ASAP PUBLICATION
■
This paper was incorrectly published ASAP on August, 10
2021 due to a production error. The paper was corrected and
the revised paper reposted on August 13, 2021.
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