Sodium Diisopropylamide in Tetrahydrofuran: Selectivities, Rates, and Mechanisms of Arene Metalations

Article abstract of DOI:10.1021/jacs.7b08734

Sodium diisopropylamide (NaDA)-mediated metalations of arenes in tetrahydrofuran (THF)/hexane or THF/Me₂NEt solutions are described. A survey of >40 benzenoid- and pyridine-based arenes with a range of substituents demonstrates the efficacy and regioselectivity of metalation. Metalations of activated disubstituted arenes and selected monosubstituted arenes are rapid at -78 °C. Rate studies of 1,3-dimethoxybenzene and related methoxylated arenes show exclusively monomer-based orthometalations with two or three coordinated THF ligands. Rate studies of the isotopic exchange of benzene and monosubstituted arenes with weakly activating groups reveal analogous di- and trisolvated monomer-based metalations. Cooperative inductive, mesomeric, steric, and chelate effects are discussed.

Full text of DOI:10.1021/jacs.7b08734

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Article
Sodium Diisopropylamide in Tetrahydrofuran:
Selectivities, Rates, and Mechanisms of Arene Metalations
Russell F. Algera, Yun Ma, and David B. Collum
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b08734 • Publication Date (Web): 26 Sep 2017
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Sodium Diisopropylamide in Tetrahydrofuran:
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Selectivities, Rates, and Mechanisms of Arene Metalations
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Russell F. Algera, Yun Ma, and David B. Collum*
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Department of Chemistry and Chemical Biology
Baker Laboratory, Cornell University
Ithaca, New York 14853–1301
E-mail: dbc6@cornell.edu
Abstract
Sodium diisopropylamide (NaDA)-mediated metalations of arenes in
tetrahydrofuran (THF)/hexane or THF/Me2NEt solutions are described. A
survey of >40 benzenoid- and pyridine-based arenes with a range of
substituents demonstrates the efficacy and regioselectivity of metalation.
Metalations of activated disubstituted arenes and selected monosubstituted
arenes are rapid at –78 °C. Rate studies of 1,3-dimethoxybenzene and
related methoxylated arenes show exclusively monomer-based
orthometalations with two or three coordinated THF ligands. Rate studies of
the isotopic exchange of benzene and monosubstituted arenes with weakly
activating groups reveal analogous di- and trisolvated monomer-based
metalations. Cooperative inductive, mesomeric, steric, and chelate effects
are discussed.
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Introduction
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In 1908, Schorigin reported that ethylsodium metalates benzene,
constituting the first example of an organosodium-mediated arene
metalation.1 Progress accelerated with seminal studies by Gilman in the
1930s and Morton in the 1940s that explored highly reactive aryl- and
alkylsodiums.2–4 Renewed activity in organosodium chemistry appeared with
the emergence of mixed-alkali-metal super bases5 and, most recently, the
structural studies of Mulvey and coworkers.6
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Of course, a number of sodium-based reagents are used routinely.
Sodium hexamethyldisilazide is illustrative and, despite a relatively low
basicity, is commonly used.7 By comparison to organolithium chemistry,
however, organosodium chemistry has been in a protracted period of
latency. Sodium diisopropylamide (NaDA) is an excellent case in point.
Although lithium diisopropylamide (LDA) is used hundreds if not thousands
of times daily, only a dozen reports on NaDA have appeared in the literature
during the intervening six decades since the first report by Levine and co-
workers in 1959.8,9 It is difficult to explain with confidence this dearth of
publications, but a recent statement online probably captures the essence of
the problem by referring to organosodium reagents as “limited in part due to
competition from organolithium compounds” and “poorly soluble."
We have begun a program to examine the synthetic, structural, and
mechanistic organosodium chemistry that centers on the chemistry of
NaDA.10 In the first of a series of papers, we showed that 1.0 M solutions of
NaDA in N,N-dimethylethylamine (DMEA) can be prepared in minutes
using technical-grade reagents (eq 1).10a Subsequent studies probed the
stability and solubility of NaDA in a range of solvents—dimers 1 and 2 are
germane to the work described below10b—as well as the reactivity of NaDA
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toward alkenes and dienes.10c Metalation of substituted arenes by NaDA
must have been examined and possibly even reported, but our failure to find
a literature example underscores a glaring omission (eq 2).11 In this paper,
we describe NaDA-mediated arene sodiation from a synthetic organic and
mechanistic perspective.12
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Na dispersion
(1)
i-Pr2NH / DMEA
i-Pr2NNa / DMEA
isoprene
1.0 M solution
15 minutes
Et
Me
Me
THF THF
N
i-Pr
i-Pr
Na
Na
i-Pr
i-Pr
i-Pr
i-Pr
Na
Na
N
i-Pr
i-Pr
N
N
N
N
THF THF
Me
Me
Et
2
1
X
X
i-Pr2NNa / THF
(2)
DMEA
or
Na(THF)n
Y
Y
hexane
Results
Methods. NaDA was prepared and purified with a modified literature
procedure.9a,10a It can be handled as a pyrophoric white solid or as a 1.0 M
solution in DMEA, both of which are stable for weeks at 25 °C and for
months at –20 °C.10a,b Control experiments showed that
NaDA/tetrahydrofuran (THF)/DMEA and NaDA/THF/hexane are
operationally indistinguishable, consistent with the weak donicity of
trialkylamines and exergonic substitution by THF.13,14 We use the two
cosolvents interchangeably but favor NaDA/THF/hexane because of our
specific interest in structural and mechanistic studies. The typical
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practitioner is likely to find NaDA/DMEA stock solutions convenient. Rate
studies of NaDA-mediated THF decomposition at 25 °C were carried out
previously;10b the decomposition is not a problem under the conditions
described herein.
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Arene metalations were monitored using 1H, 2H, and 19F NMR or in
situ IR spectroscopies.15,16 By habit and protocols tied to rate studies, we
routinely carry out metalations with 0.10 M NaDA, although metalations of
0.50–1.0 M arene occur without detectable precipitation of the arylsodiums
in most instances.17 Arenes can be cataloged as those that metalate
instantaneously at –78 °C (Chart 1), slowly enough to monitor at –78 °C
(Chart 2), detectably only through isotopic exchange (Chart 3), and
destructively (Chart 4). Metalations of the substrates in Charts 1–4 using
other bases have been reported.12 We have not observed any evidence of
polymetalation.
Chart 1. Substrates that rapidly metalate.
F
F
F
Cl
Cl
Cl
F
F
Cl
Cl
F
3
4
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8
(10)
I
F
Cl
F
CF3
CF3
CF3
CF3
F
CF3 Cl
(1)
F3C
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Cl
O
N
Cl
N
N
N
CF3
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Chart 2. Substrates that metalate at measurable rates.
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OMe
OMe
OMe
MeO
OMe
MeO
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9
OMe
N
OMe
N
OMe
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Chart 3. Substrates that transiently metalate.
NEt2
OMe
NMe2
(1)
(1.5)
(1)
(2.4)
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25
26
27
CF3
O
Me
Me
OMe
N
MeO
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Chart 4. Substrates that degrade on metalation.
Cl
Br
F
Br
Br
Br
CF3
N
CF3
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O
Br
N
F
Cl
N
N
Br
N
N
F
N
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Regioselectivity and Reversible Metalation. The regioselectivities
for the substrates in Charts 1 and 3 are implicitly ortho or doubly ortho.
Arrows denote selectivities that are ambiguous or less obvious. Whether the
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selectivities are kinetically or thermodynamically controlled cannot be
ascertained unless an equilibration is explicitly detected. A rare example is
the ~5:1 selectivity for the metalation of 13 at –116 °C that reverses to a
1:10 selectivity on standing at –116 °C (eq 3 and Chart 1). Such an
isomerization would be undetectable at –78 °C.
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Na(THF)n
Cl
CF3
Cl
CF3
Cl
CF3
NaDA
–116 °C
(3)
–116 °C
kinetic: 5:1
thermodynamic: 1:10
(THF)nNa
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Kinetics and Mechanism of Arene Metalation.18 The muted
reactivity of arenes in Chart 2 allowed us to monitor rates under pseudo-
first-order conditions in which the substrate was the limiting reagent (0.010
M). The metalation of 1,3-dimethoxybenzene (20, eq 4) at –78 °C by NaDA
in THF/hexane follows a clean decay to partial conversion at equilibrium
(Figure 1). A plot of initial rate versus THF concentration (Figure 2) shows a
linear dependence with a substantial non-zero intercept. The rates monitored
versus NaDA concentration (Figure 3) afford an approximate half-order
dependence. The idealized rate law19 (eq 5) and assignment of NaDA as
tetrasolvated dimer 210b are consistent with the dominant disolvated-
monomer-based metalation depicted generically in eq 6.20 The collective
data on THF dependencies (below) suggest that the first-order dependence is
likely to be a primary shell solvation step consistent with low levels of an
intervening trisolvated-monomer-based metalation (eq 7).
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0
500 1000 1500 2000
time (s)
Figure 1. Plot of 1,3-dimethoxybenzene (20, ArH) concentration versus
time for stoichiometric orthometalation with 0.10 M NaDA in 5.83 M
THF/hexane at –78 °C. The curve depicts an unweighted least-squares fit to
the function18,21 [ArH] = {[ArH]s1–n + k(n–1)t}1/(1–n) + [ArH]∞: [ArH]s =
0.0368 ± 0.0004; n = 0.71 ± 0.03; k = (4.1 ± 0.4) × 10–4; [ArH]∞ = 0.0616 ±
0.0003. The deviation from 1.5-order behavior (first order in arene and one-
half order in NaDA) is likely due to mild autocatalysis.
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10 12
[THF] (M)
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Figure 2. Plot of initial rate versus THF concentration for the
orthometalation of 0.010 M 1,3-dimethoxybenzene (20) with 0.10 M NaDA
at –78 °C. The curve depicts an unweighted least-squares fit to the function
f(x) = ax + b: a = 0.19 ± 0.04; b = 2.5 ± 0.03.
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8
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2
0
0.00
0.10
0.20
0.30
[NaDA] (M)
Figure 3. Plot of initial rate versus NaDA concentration for the
orthometalation of 0.010 M 1,3-dimethoxybenzene in 6.0 M THF/hexane at
–78 °C. The curve depicts an unweighted least-squares fit to the function
f(x) = axb: a = 15 ± 2; b = 0.62 ± 0.07.
OMe
OMe
Keq[THF]n
+ i-Pr2NH (4)
+ 1/2 (i-Pr2NNa)2(THF)4
Na(THF)2+n
OMe
OMe
20-Na
20
2
–d[ArH]/dt = (k[THF]0 + k’[THF]1)[A2S4]1/2[ArH]1
(5)
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1/2 A2(THF)4 + ArH
1/2 A2(THF)4 + THF + ArH
[A(THF)2·ArH]‡
[A(THF)3·ArH]‡
(6)
(7)
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Rate studies using 1,2,4-trimethoxybenzene (21) show that metalation
occurs threefold faster than 20 via an otherwise analogous mechanism and
incomplete conversion at equilibrium (Supporting Information). Unlike the
metalation of 20, however, metalation of high concentrations of 21 reveals
autocatalysis in the form of a sigmoidal decay (Figure 4). Decays at lower
arene concentrations are nearly exponential (see Figure 4, inset). An
approximate22 first-order dependence of initial rates on ArNa is consistent
with the intermediacy of a fleeting NaDA/ArNa mixed aggregate (eq 8).23
Curiously, arylsodium 21-Na also catalyzes the metalation of 20, whereas
20-Na does not catalyze the metalation of 21.
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0.08
0.06
0.04
0.02
0.00
0
50
100 150 200
time (s)
Figure 4. Plot of 1,2,4-trimethoxybenzene (21, ArH) concentration versus
time for the metalation of 0.080 M ArH with 0.10 M NaDA in neat THF at –
78 °C. Inset: plot of arene concentration versus time (0–1200 s) for the
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metalation of low concentrations (0.010 M) of ArH with 0.10 M NaDA in
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neat THF at –78 °C.
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+ArH
9
1/2 2 + ArNa
[(i-Pr)2NNa•ArNa]
2 ArNa
(8)
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Kinetics and Mechanism of Isotopic Exchange. The influence of
arene substituents on the rates, mechanisms, and selectivities of metalation
was examined by monitoring deuterium exchange (eq 9) for substrates that
metalate only transiently (see Chart 3).24 Monitoring initial rates by 2H NMR
spectroscopy precludes multiple exchanges and minimizes the slower but
detectable exchange with α protons in THF.10b The regiochemistries (arrows
in Chart 3) attest to competitive steric, chelation, inductive, and π effects
(discussed below).
NaDA
ArH + i-Pr2ND
ArD + i-Pr2NH
(9)
(excess)
ArH: PhNEt2 < PhNMe2 < PhH < PhOMe < PhCF3 < 29
krel: (1.0) (1.5)
(10) (5 × 103) (104) (2 × 104)
Rate studies show approximate half-order NaDA dependencies in all
cases, which signify monomer-based metalations. Plots of rate versus THF
concentration show substrate-dependent contributions of zeroth- and first-
order dependencies attributed to the reactions of di- and trisolvated-
monomer-based metalations (Figures 5–8). PhNEt2 markedly attenuates
ortho metalation rates relative to PhNMe2 while leaving meta metalation
unchanged. PhCF3 shows evidence of exchange into the para position but
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only at elevated temperature (–20 °C). The Supporting Information has full
details.
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2.5
2.0
1.5
1.0
0.5
0.0
0
2
4
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10
[THF] (M)
Figure 5. Plot of initial rate versus THF concentration for the isotopic
exchange of 0.23 M benzene with 0.10 M NaDA and 1.04 M i-Pr2ND in
hexane cosolvent at 25 °C. The curve depicts an unweighted least-squares fit
to the function f(x) = axb: a = 0.12 ± 0.02; b = 1.30 ± 0.02.
1.4
1.2
ortho
1.0
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meta
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0.2
0.0
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[THF] (M)
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Figure 6. Plot of initial rate versus THF concentration for the isotopic
exchange of 0.44 M N,N-dimethylaniline (25) with 0.10 M NaDA and 0.79
M i-Pr2ND in hexane cosolvent at 25 °C. The curves depict unweighted
least-squares fits to the function f(x) = ax + b: ortho: (a = 0.08 ± 0.02; b =
0.6 ± 0.1); meta: (a = 0.09 ± 0.02; b = 0.2 ± 0.1).
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ortho
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meta
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0
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[THF] (M)
Figure 7. Plot of initial rate versus THF concentration for the isotopic
exchange of 0.45 M α,α,α-trifluorotoluene (28) with 0.10 M NaDA and
0.79 M i-Pr2ND in hexane cosolvent at –40 °C. The curves depict
unweighted least-squares fits to the function f(x) = ax + b: ortho: (a = 0.80 ±
0.02; b = 0.6 ± 0.1); meta: (a = 0.18 ± 0.02; b = 0.1 ± 0.1).
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[THF] (M)
Figure 8. Plot of initial rate versus THF concentration for the ortho-selective
isotopic exchange of 0.32 M 4,4-dimethyl-2-phenyl-2-oxazoline (29) with
0.10 M NaDA and 0.79 M i-Pr2ND in hexane cosolvent at –40 °C. The curve
depicts an unweighted least-squares fit to the function f(x) = ax + b: a = 0.09
± 0.1; b = 6.8 ± 0.9.
Discussion
We examined NaDA-mediated metalations of >40 arenes grouped by
those that metalate instantaneously at –78 °C (see Chart 1), at tractable rates
(see Chart 2), via fleeting arylsodiums (see Chart 3), and destructively (see
Chart 4). Collectively, these metalations allow us to confront issues and
questions recognizable to those versed in base-mediated arene
functionalization.10
The Case for Sodium. NaDA is easy to prepare as stable 1.0 M
solutions in trialkylamines (DMEA) and is readily isolated as a white
solid.10a,b The steric demands of trialkylamines13,14 allow for exergonic
substitution by standard ethereal ligands either before or after metalation.
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Adding >3 equiv THF to NaDA/DMEA quantitatively converts DMEA-
solvated dimer 1 to THF-solvated dimer 2.10b Rates of arene metalations
using NaDA/THF are often so rapid that they cannot be studied
mechanistically. The lack of previously cited NaDA-mediated arene
metalations underscores the degree to which the community may have
overlooked organosodium chemistry. That said, the full advantages of NaDA
will take time to emerge.
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Regioselectivities. The selectivities in Charts 1–3 are singly or doubly
ortho unless otherwise indicated by arrows. This story is not so simple,
however. The issue of regiochemical equilibration in ortholithiations has
surfaced previously,26 been studied mechanistically,27 and emerges again
here. Explicit kinetic versus thermodynamic control was documented for
arene 13 (eq 3). However, we cannot rule out the possibility that many
arylsodiums equilibrate rapidly; kinetic versus thermodynamic preferences
remain unresolved. This ambiguity is more pervasive than researchers may
realize in many studies of regioselectivity. From reviewing limited data, we
suspect—it is more of a hunch than an observation—that isomerization may
be more prevalent with NaDA than LDA.
Over the decades, practitioners of orthometalations have surveyed
relative directing effects of arene substituents largely through internal
competitions of ortho-, meta-, and para-disubstituted arenes 42, 43, and 44,
respectively.12 Empirically observed fast versus slow metalations add to the
story.
X
Y
X
Y
X
Y
43
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42
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These experiments are well suited to researchers who want
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orthometalations to be predictable. However, there are latent approximations
in using such disubstituted arenes because inductive, resonance, steric, and
chelation effects are not always restricted to the ortho position. How do
meta and para substituents influence the rates of ortho metalations? In short,
the effects are additive and underdetermined in such seemingly simple
regiochemical competitions. It is in this context that we have become
enamored with the isotopic exchange studies of the transiently metalated
substrates in Chart 3.24,25 Monosubstituted arenes present no such
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additivities, and observable meta and para exchanges reveal long-range
effects that cannot be ignored. We should add that entirely regioselective
orthometalations of arenes 27 and 29 tell us nothing about these long range
effects and show only that the influence at the ortho position is large by
comparison (dominant); the rate of benzene exchange provides a benchmark
for the rates of meta and para metalation.
We discerned separate contributions at play: (1) PhCF3 (28) shows a
distribution suggesting that CF3 exerts a dominantly inductive influence, as
noted by Mulvey using nBuNa11; (2) a comparison of the relative rates of
benzene (24) and PhNMe2 (25) reactions shows that anilines are deactivated
toward metalation (even accounting for statistics), with the most marked
inhibition occurring at the para position suggesting a destabilizing resonance
effect; and (3) a comparison of PhNMe2 (25) and PhNEt2 (26) confirms that
steric effects retard orthometalation, tacitly promoting meta substitution. The
conclusions that should surprise few are as follows: resonance effects inhibit
ortho and para metalation; inductive effects promote ortho, meta, and para
metalation in that order; steric effects inhibit only orthometalation; and
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chelation (substituent coordination to sodium) promotes only
orthometalation.
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Decompositions. There were, of course, a few failures (see Chart 4).
Benzyne formation poses a problem in some cases (unless it is the targeted
outcome).28 The stabilized ortho-halo arylsodiums derived from most
substrates in Chart 1 illustrate that elimination to form benzyne is not a
chronic problem. In several cases, we saw limited darkening of the solutions
that seemed to accompany decomposition, but the NMR spectra of the
arylsodiums and successful deuterations revealed no major problems.
Although the failures in Chart 4 could stem from benzyne formation,
we cannot exclude [Ar–Br–NR2]– adducts,29 electron-transfer-based
reductions,30 or migration (halogen dancing).31 One cannot help but notice
bromoarenes appear to be problematic. Arenes 38–40 share a 3-halopyridine
motif that may present special problems in contrast to the successful 2-halo
arene metalations in Chart 1; enhanced electrophilicity may be the cause.
Nucleophilic addition to pyridines, particularly self-condensation,32 is a
problem we hoped to avoid.
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The CF3 substituent seems particularly sensitive to destruction,33
possibly owing to the formation of benzocyclopropene as reported by
Billups.33b Interestingly, PhCF3 should be highly sensitive to decomposition,
but NaDA-mediated isotopic exchange was readily achieved. Several doubly
activated forms including 14 and 16 showed darkening but no direct
evidence of destruction.
Oxazoline 41 appears to undergo facile elimination of the saturated
heterocycle backbone, which often elicits the use of 4,4-dimethylated analog
29. We are the only group to report the LDA-mediated orthometalation of
41.34 Suspecting that this result might be erroneous, we repeated the
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metalation and confirmed our mistake (one likely caused by inadequate
supervision).34 Nonetheless, alkyllithiums and lithium 2,2,6,6-
tetramethylpiperidide orthometalate 41 without competing
9
decomposition.35,36
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Mechanisms. All rate studies of observable metalations of 20 and 21
as well as of isotopic exchange via fleeting anions derived from 24–30 show
approximately half-order dependencies on NaDA consistent with monomer-
based metalations. Plots of rate versus THF concentration showing non-zero
intercepts and linear dependencies on THF concentration are consistent with
di- and trisolvated monomers, respectively.18 Minor THF dependencies
could be ascribed to medium effects, but the absence of dependence in some
cases (see Figure 8) and striking dependence in others (see Figures 5 and 7)
argue strongly for primary shell solvation. We add that secondary-shell
effects are generally small when using lithium bases.18,37 We can glean some
insights about substituent dependencies by noting the relative contributions
of the two solvation states.
The metalation of benzene, a cornerstone of any discussion of arene
metalation, occurs via the trisolvated-monomer-based mechanism shown by
density functional theory (DFT) computations38 to be 45. The slight upward
curvature in the plot in Figure 5 suggests a contributing tetrasolvate.
Although DFT data are unsupportive, we are reluctant to dismiss such a
mechanism because we have found transition states based on five- and even
six-coordinate sodiums to be computationally viable in other instances.10c
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H
7
8
(i-Pr)2N Na
THF
THF
THF
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45
Metalations of 20 and 21 with meta-disposed methoxy moieties yield
a mixture of di- and trisolvates consistent with encroaching steric demand.
DFT computations show discrete MeO–Na interactions in both 46 and 47
and predict a distinct preference for trisolvation (eq 10) that is not borne out
experimentally (see Figure 2). Analogous studies of n-butyllithium/N,N,N,N-
tetramethylethylenediamine-mediated metalations showed no experimental
or computational evidence of methoxy-lithium contacts. Anisole, a less
congested variant of 20 and 21, shows MeO–Na contacts and no significant
preference for the di- vs. trisolvate experimentally or computationally (eq
11). The somewhat baffling quantitative difference in eqs 10 and 11 was
explored extensively, but no obvious explanation was found.
Me
Me
O
O
Me
Me
–5.0 kcal/mol
O
O
(10)
H
H
(i-Pr)2N Na
(i-Pr)2N Na
THF
THF
THF
THF
THF
46
47
+0.1 kcal/mol
Me
Me
O
O
(11)
H
H
(i-Pr)2N Na
(i-Pr)2N Na
THF
THF
THF
THF
THF
48
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PhCF3 behaves as an inductively activated benzene, facilitating
metalations at all positions. Orthometalation represents a potential battle of
steric inhibition versus activation through induction and Na–F interaction
(chelation). DFT computations support such an interaction (50), but the
resulting regioselectivity suggests that it cannot be highly stabilizing (eq 12).
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CF3
CF3
F
+3.1 kcal/mol
+1.7 kcal/mol
(12)
H
F
F
H
H
THF
THF
THF
THF
(i-Pr)2N Na
(i-Pr)2N Na
(i-Pr)2N Na
THF
THF
THF
THF
THF
50
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52
Metalations of anilines 25 and 26 are especially interesting. Anilines
are notoriously poor directing groups, a fact readily ascribed to both
prominent steric effects and the weak Lewis basicity of the dimethylamino
moiety.12 Although early studies using alkylsodiums suggest that anilines are
acidic relative to benzene,2 we found that both 25 and 26 metalate more
slowly than benzene. DFT computations of orthometalation (53) show
evidence of an N–Na contact, but it could merely reflect the minimization of
steric effects. The de facto preference for meta metalation results from
inhibited ortho and para metalation. Isotopic exchange of the benzene-like
meta position occurs by di- and trisolvated monomers in contrast to the
absence of disolvated-monomer-based metalation of benzene and gives us
pause.
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NMe2
H
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(i-Pr)2N Na
THF
THF
THF
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53
Oxazoline 29 appears to be a prime candidate for a chelation-directed
orthometalation, which is implicated by high rates and a dominant
disolvated-monomer-based pathway. Previous studies of the lithium analog
suggest that the N–Li contact is preferred relative to the O–Li contact.39,40
Indeed, DFT computations show a >6 kcal/mol preference for the N–Na
interaction shown in 54 despite the steric demands imparted by the methyl
moieties. The proton transfer in transition structure 54 displays significant
distortion, with the arene C–H bond deviating 17° degrees out of the
benzene plane accompanied by 19° rotation of the oxazoline moiety relative
to the benzene fragment. This potentially strong directing group appears to
be laboring to achieve optimal alignment.
O
N
H
Me
Me
THF
THF
(i-Pr)2N Na
54
Conclusion
NaDA-mediated metalations of arenes are much faster than those with
LDA. However, time will tell whether investigators facing specific
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challenges will find such accelerations advantageous. That NaDA is trivial
to prepare and handle ought to bolster its synthetic appeal. We also suspect
that reactions of the resulting arylsodiums are ripe for development.
Metathesis with other metal salts such as copper chloride or zinc chloride for
subsequent couplings will occur under “salt-free” conditions given the
insolubility of NaCl.41,42 In anticipation of such interest, we began studying
the solution structures of the arylsodiums generated herein. Thinking that the
task would be easy, we discovered it is a research project in its own right.
For now, we can say that NaDA-mediated metalations of arenes generally
work well and are mechanistically tractable.
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Experimental
IR spectroscopic analyses. IR spectra were recorded using an in situ
IR spectrometer fitted with a 30-bounce, silicon-tipped probe. The spectra
were acquired in 16 scans at a gain of 1 and a resolution of 4 cm–1. A
representative reaction was carried out as follows: The IR probe was inserted
through a nylon adapter and O-ring seal into an oven-dried, cylindrical flask
fitted with a magnetic stir bar and a T-joint. The T-joint was capped with a
septum for injections and a nitrogen line. After evacuation under full
vacuum, heating, and flushing with nitrogen, the flask was charged with
NaDA (60.4 mg, 0.49 mmol) in THF/hexane (4.9 mL) and cooled in a dry
ice–acetone bath prepared with fresh acetone. After recording a background
spectrum, a stock solution of arene 20 (100 µL, 0.049 mmol) was added with
stirring. For the most rapid reactions, IR spectra were recorded every 6 s
with monitoring of the absorbance at 1493 cm–1 over the course of the
reaction.
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NMR Spectroscopy. NMR samples for reaction monitoring were
routinely prepared using stock solutions of NaDA and flame-sealed under
partial vacuum. DMEA-free solutions of NaDA with added ligands used
DMEA-free crystallized NaDA. Standard 1H, 2H, and 13C NMR spectra were
recorded on a 500 MHz spectrometer at 500, 76.7, and 125.7 MHz,
respectively. The 1H, 2H, and 13C resonances were referenced to the CH2O
resonance (3.58 ppm), CD(H)O resonance (3.58 ppm), and CH2O resonance
(67.57 ppm) of THF at –80 °C, respectively.
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DFT Computations. DFT calculations were carried out at the
B3LYP/6–31G(d) level with single-point calculations at the MP2 level of
theory.38 Transition structures each had a single negative frequency.
Arene Metalations: Method A. A representative reaction was carried
out as follows: Sodium dispersion in toluene (3.0 mL, 35 mmol) in a 15 mL
pear-shaped flask was washed three times with DMEA (2.0 mL each) using
a syringe to remove of the supernatants. A final aliquot of DMEA was added
(3.6 mL) followed by diisopropylamine (1.05 mL, 7.5 mmol). After cooling
to 0 °C, isoprene (380 mL, 3.75 mmol) was added. The solution was allowed
to warm to rt over the course of 20 minutes, after which the stirring was
halted and insoluble materials were allowed to settle providing a yellow
supernatant. A dried vial was charged with this stock solution (2.9 mL, 4.4
mmol), to which THF (5.0 mL) was added and cooled to –78 °C. Neat 1,2-
dichlorobenzene (382 mL, 3.4 mmol) was added with stirring for 30 sec and
subsequently quenched with 1.00 mL MeOD. After warming to rt, the
reaction mixture was diluted with water and pentane. The organic layer was
washed with water (4 × 5 mL), dried over sodium sulfate, and concentrated.
The crude product was chromatographed in neat pentane (Rf = 0.7) to
provide 1,2-dichlorobenzene (270 mg, 55% mass recovery) with 80%
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deuteration at the ortho position. The extent and regiochemistry of proton
loss was taken to represent the metalation event.
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Arene Metalations: Method B. A representative reaction was carried
out as follows: A dried vial flushed with argon was sequentially charged
with solid NaDA (49 mg, 0.400 mmol) and THF (1.00 mL) and cooled to –
78 °C. Neat 1,2-dichlorobenzene (42 µL, 0.38 mmol) was added with
stirring for 10 s and subsequently quenched with 500 µL MeOD. Neat
cyclohexene (100 µL) was added to the flask as an internal standard. After
the sample was warmed to rt, a portion was transferred to an NMR tube for
analysis as noted above.
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Acknowledgments. We thank the National Institutes of Health
(GM039764) for support.
Supporting Information: Spectroscopic, kinetic, and computational
data and authors for reference 38. This material is available free of charge
via the Internet at http://pubs.acs.org.
Author Information
David B. Collum
*dbc6@cornell.edu
Notes
The authors declare no competing financial interests.
References and Footnotes
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1. Schorigin, P. Ber. 1908, 41, 2711.
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9
2. Benkeser, R. A.; Foster, D. J.; Sauve, D. M.; Nobis, J. F. Chem. Rev.
1957, 57, 867.
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25
26
27
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35
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41
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3. (a) Schlosser, M. Angew. Chem., Int. Ed. 1964, 3, 287. (b) Schlosser, M.
Angew. Chem., Int. Ed. 1964, 3, 362. (c) Mordini, A. In Comprehensive
Organometallic Chemistry III; Mingos, D. M. P.; Crabtree, R. H., Eds;
Elsevier, 2007, vol. 9, p 3. (d) Annual surveys: Glaze, W. H. Organometal.
Chem. Rev. 1971, 8, 319 and references cited therein. (e) Jonczyk, A.;
Kowalkowska, A. In Science of Synthesis, 8b: Category 1, Organometallics;
Majewski, M. and Snieckus, V., Eds. Thieme: New York, 2006, vol 8b, p
1141.
4. For an interesting historical perspective on organoalkali metal chemistry,
see: (a) Seyferth, D. Organometallics 2006, 25, 2. (b) Seyferth, D.
Organometallics 2009, 28, 2.
5. Schlosser, M. Pure Appl. Chem. 1988, 60, 1627.
6. Mulvey, R. E.; Robertson, S. D. Angew. Chem., Int. Ed. 2013, 52, 11470.
(b) Garden, J. A.; Armstrong, D. R.; Clegg, W.; García-Alvarez, J.; Hevia.
E.; Kennedy, A. R.; Mulvey, R. E.; Robertson, S. D.; Russo, L.
Organometallics 2013, 32, 5481.
7. Sodium hexamethyldisilazide can be viewed as an LDA surrogate, but it
is limited by an approximately 10 pKa unit lower basicity: Watson, B. T.;
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Lebel, H. Sodium Hexamethyldisilazide In e-EROS Encyclopedia of Reagents for
Organic Synthesis; Ed: Paquette, L.; John Wiley & Sons, New York; 2004.
7
8
9
8. Raynolds, S.; Levine, R. J. Am. Chem. Soc. 1959, 82, 472.
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9. (a) Barr, D.; Dawson, A. J.; Wakefield, B. J. J. Chem. Soc., Chem.
Commun. 1992, 204. (b) For an attempted comprehensive bibliography of
NaDA, see reference 10a.
10. (a) Ma, Y.; Algera, R. F.; Collum, D. B. J. Org. Chem. 2016, 81, 11312.
(b) Algera, R. F.; Ma, Y.; Collum, D. B. J. Am. Chem. Soc. 2017, 139, 7921.
(c) Algera, R. F.; Ma, Y.; Collum, D. B. J. Am. Chem. Soc. 2017, 139,
11544.
11. (a) For other forms of orthosodiations, see references 1–6. (b) Pannell
and coworkers documented improved efficacy of NaDA when compared
with LDA for the metalation of a cyclopentadienyl iron complex: Munguia,
T.; Bakir, Z. A.; Cervantes-Lee, F.; Metta-Magana, A.; Pannell, K. H.
Organometallics 2009, 28, 5777.
12. (a) Gschwend, H. W.; Rodriguez, H. R. Org. React. (N. Y.) 1979, 26, 1.
(b) Snieckus, V. Chem. Rev. 1990, 90, 879. (c) Ager, D. J.; Prakash, I.;
Schaad, D. R. Chem. Rev. 1996, 96, 835. (d) Clayden, J. Organolithiums:
Selectivity for Synthesis; Tetrahedron Organic Chemistry, Vol. 23;
Pergamon: Oxford, 2002. (e) Haag, B.; Mosrin, M.; Ila, H.; Dr. Vladimir
Malakhov, V.; Knochel, P. Angew. Chem., Int Ed. 2011, 50, 9794. (f)
Schlosser, M. Angew. Chem. Int. Ed. 1998, 110, 1496.
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13. For early studies revealing poor coordination of trialkylamines to
organolithium aggregates, see: (a) Settle, F. A.; Haggerty, M.; Eastham, J. F.
J. Am. Chem. Soc. 1964, 86, 2076. (b) Lewis, H. L.; Brown, T. L. J. Am.
Chem. Soc. 1970, 92, 4664. (c) Brown, T. L.; Gerteis, R. L.; Rafus, D. A.;
Ladd, J. A. J. Am. Chem. Soc. 1964, 86, 2135. (d) Quirk, R. P.; Kester, D. E.
J. Organomet. Chem. 1977, 127, 111.
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14. Discussion of cone angle and steric demands of trialkylamines: (a)
Seligson, A. L.; Trogler, W. C. J. Am. Chem. Soc. 1991, 113, 2520. (b) Choi,
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