Disodium Salts of Pseudoephedrine-Derived Myers Enolates: Stereoselectivity and Mechanism of Alkylation

Article abstract of DOI:10.1021/jacs.9b08176

Pseudoephedrine-derived dianionic Myers enolates were generated using sodium diisopropylamide (NaDA) in THF solution. The reactivities and selectivities of the disodium salts largely mirror those of the dilithium salts but without the requisite large exce

Full text of DOI:10.1021/jacs.9b08176

Article
pubs.acs.org/JACS
Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Disodium Salts of Pseudoephedrine-Derived Myers Enolates:
Stereoselectivity and Mechanism of Alkylation
Yuhui Zhou, Ivan Keresztes, Samantha N. MacMillan, and David B. Collum*
Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell University, Ithaca, New York 14853−1301, United
States
S
* Supporting Information
ABSTRACT: Pseudoephedrine-derived dianionic Myers eno-
lates were generated using sodium diisopropylamide (NaDA)
in THF solution. The reactivities and selectivities of the
disodium salts largely mirror those of the dilithium salts but
without the requisite large excesses of inorganic salts (LiCl) or
mandated dilute solutions. The disodium salts require careful
control of temperature to preclude deleterious aggregate aging effects traced to changes in the aggregate structure and
intervening O-alkylations. Structural studies and density functional theory (DFT) computations show a dominant highly
symmetric polyhedron quite different from the lithium analogue. No enolate−NaDA mixed aggregates are observed with excess
NaDA. Rate studies show an alkylation mechanism involving an intervening tetramer−monomer pre-equilibrium followed by
rate-limiting alkylation of tetrasolvated monomers. DFT computations were conducted to explore the possible influences on
stereochemistry. A crystal deriving from samples aged at ambient temperature contains six dianionic subunits and two
monoanionic (alkoxide-only) subunits. A new preparation of concentrated solutions of NaDA in THF solution is described.
but highly reactive, aggregates converge to a single inert
octalithiated aggregate.5 Of several possible 16-vertex polyhedra
(Chart 1),6 2 was shown to have a core corresponding to 5 (M
INTRODUCTION
■
Myers and co-workers have shown that dianions of type 2,
derived from acylated pseudoephedrines (1) and lithium
diisopropylamide (LDA), alkylate with high yields and
stereoselectivities (eq 1).1 Alkyl halides and epoxides add
a
Chart 1. Polyhedra of Octametalated Species
a
M = Li or Na.
= Li). Enolate 2 in the presence of 5.0 equiv of LiCl forms a
mixed aggregate that eluded our best efforts at assignment but
displayed high reactivities and excellent overall yields, as
previously described by Myers.
We sought to develop a modified alkylation protocol that
would omit the LiCl from the reaction mixture. Although the
unaged, LiCl-free enolates were orders of magnitude more
reactive than the corresponding aged samples containing
exclusively 5, we were unable to coax alkylations beyond 70%
conversion, owing to the onset of aging.7,8 Thus, a LiCl-free
alkylation protocol seemed to call for a fundamentally different
strategy.
with opposite facial selectivities for reasons that are not yet
understood. Removal of the pseudoephedrine auxiliary is
facilitated by anchimeric assistance.2 Second-generation
enolates (4) based on a diphenyl-substituted amino-ethanol
backbone (3) are also effective, obviating the need to work with
a controlled substance.3 Of note, however, both protocols
require the addition of ≥5.0 equiv of anhydrous LiCl, which
imposes relatively low (∼0.10 M) enolate concentrations.
These two limitations, while of minor inconvenience in an
academic setting, add significant cost on pharmaceutical plant
scales.4
We previously examined the structures and reactivities of 2.
The low conversions in the absence of LiCl were traced to aging
effects, in which an exceedingly complex mixture of ill-defined,
Received: July 30, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.9b08176
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
We describe herein the chemistry of disodiated enolate 8,
generated using sodium diisopropylamide (NaDA) in THF.
Alkylations proceed in high yields and selectivities at up to 0.50
M enolate without added salts (eq 2). We document two
solution less viscous and easily syringed. Given that the THF
solution of NaDA can be placed over fresh sodium without
evidence of gelling, we infer that the surface of the spent sodium
must somehow be important, and possibly the isoprene dimer
byproduct is involved. Titration with diphenylacetic acid15
routinely showed 1.6−1.8 M titer (approximately 80−90% of
the theoretical titer). The entire preparation requires
approximately an hour. We have prepared 200 mmol with no
evidence of an exotherm, but suggest monitoring the internal
reaction temperature in case an exotherm emerges.
Reactivity and Selectivity. Exposure of 1 (0.040 M) to 2.5
equiv of NaDA in neat THF at −78 °C leads to the
disappearance of the IR absorbance of 1 at 1649 cm−1 and its
replacement with the absorbance of disodium enolate 8 at 1620
cm−1 within 3 min. At higher temperatures, deleterious enolate
aging effects intervene (vide infra). Quantitative monitoring of
the alkylation of 8 by IR spectroscopy is challenging owing to
overlapping absorbances; however, 1H NMR spectroscopy
reveals that alkylations with 2.0 equiv of highly reactive alkyl
halides, such as benzyl bromide (Table 1, entry 1) or allyl
distinct aging effects that influence structure and reactivity, but
both are mitigated through adequate temperature control.
Structural studies reveal that unaged disodium enolate 8 is
tetrameric, with either an octagonal prismatic or a stacked-cube
core (Chart 1, 6 or 7). Rate and computational studies reveal
the mechanism of alkylation.9,10 A new preparation of 1.6−1.8
M NaDA directly in THF solution is also notable.
Table 1. Alkylation of Enolate 8 (Equation 2)
entry
R−X
temp, time
selectivity % conv
yield
RESULTS AND DISCUSSION
■
1
2
3
4
5
6
BnBr
−78 °C, 10 min
−78 °C, 10 min
−78 °C, 48 h
>50:1
>50:1
>50:1
>50:1
>50:1
>50:1
>99%
94%
94%
92%
84%
96%
90%
92%
88%
80%
NaDA Preparation. The NaDA used in these studies was
prepared according to several different methods. We had
previously modified11a a procedure first reported by Wake-
field12 involving reduction of diisopropylamine with sodium
dispersion and isoprene. Although Wakefield originally
deposited solid NaDA, we generate 1.0 M solutions of NaDA
in N,N-dimethylethylamine (DMEA) that can be stored for
months with refrigeration. For the structural and rate studies,
we recrystallize and store solid NaDA with refrigeration, but
allyl bromide
n-BuBr
n-BuI
−40 °C, 1.0 h
i-BuI
−40 °C, 2.0 h
a
BrCH2CO2-t-Bu −78 °C, 3.5 h
<50%
a
With slow warming to 20 °C.
bromide (entry 2), occur within 5 min at −78 °C. Less reactive
saturated alkyl halides such as n-BuI (entry 4) require elevated
temperatures (−40 °C) or protracted reaction times. n-BuBr
requires 48 h at −78 °C to attain high conversion (entry 3).
Even the shortened reaction times for the alkyl iodides showed
some sacrifice of percent conversion and consequent erosion of
isolated yield. Attempts to force such recalcitrant alkylations
with excessive warming cause O-alkylations (10 and 11), which
can be largely mitigated by controlling temperature and
minimizing the excess of alkylating agent. Product assignments
in Table 1 were based on those reported by Myers.1 We hasten
to add that the isolated yields reported in Table 1 are not
corrected for recovered starting material.
this added precaution does not significantly affect reactivity.11
benchtop protocol using NaDA/DMEA with added THF,
however, was not effective owing to an unusually high (third-
order) THF dependence (vide infra).
A
We explored benchtop procedures that would require no
specialized inert atmosphere equipment. Under Lochmann’s
conditions in which n-BuNa is precipitated by adding n-BuLi to
tert-BuONa in hexanes before adding diisopropylamine, we
encountered problems in decanting the supernatant owing to
the finely divided precipitate.13 The Wakefield protocol
involving sodium dispersion mediated by isoprene was readily
adapted to neat THF to afford up to 1.7 M stock solutions of
NaDA that are stable for same-day use, provided that they are
kept at 0 °C (t1/2 = 1.0 h at 25 °C in neat THF; t1/2 ≫5 h at 0
°C in neat THF).11b,14 However, the sodium dispersion made
the decanting step challenging.
The optimized preparation entailed using freshly cut large
pieces of sodium (>100 mg) that are often more available than
the dispersion, and the decanting is trivial requiring no special
precautions. The reaction is stirred at 0 °C for 45 min.
Empirically, when the reaction is finished, the shiny sodium
surface darkens. There is one critical and somewhat
unexplainable protocol: the supernatant must be removed
from the sodium when the reaction is complete to prevent
formation of a gel accompanied by graying (possibly NaH),
which becomes visible within several hours. Once the
supernatant is added to a new vessel, it can be stored at 0 °C
for at least 5 h or at −20 °C for 24 h without gelling or
measurable loss of titer. The titer drops by 5% within 48 h at
−20 °C. If stored at −20 °C, warming to 0 °C makes the
We observed a reversal of stereochemistry in the epoxide
addition, as previously reported by Myers in the context of the
lithium enolates (eq 3). Once again, the modest yields trace to
B
DOI: 10.1021/jacs.9b08176
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Figure 1. Partial 13C{1H} NMR spectra of a solution of 0.30 M 8 in neat (12.3 M) THF-d8 recorded at −80 °C: (A) aged at −80 °C overnight; (B)
aged at −30 °C for 20 min; and (C) aged at 0 °C for 20 min.
incomplete conversion, but in these reactions, the losses are
considerable. Fortunately, excess epoxide does not cause O-
alkylation; thus we could allow the samples to warm to force
higher percent conversions. The highest yields were obtained
when the reaction was warmed from −80 to 0 °C over a period
of 18 h. However, the Myers lithium-based protocol provides
decidedly higher yields.
ROESY)19 to establish critical spatial relationships. Density
functional theory (DFT) computations at the M06-2X level of
theory were conducted for both geometry optimizations and
single-point calculations. The standard 6-31G(d) basis set was
used for geometry optimizations whereas the expanded basis set
6-311+G(2d,p) was used for single point calculations.20,21 Most
of these data are archived in the Supporting Information.
The first notable structural feature of 8 is that it has a single
magnetically distinct subunit (Figure 1A). This contrasts with
dilithium salt 2, which manifests two magnetically distinct
subunits in equal (2:2) proportions. While not self-evident on
simple inspection, prismatic core 5 observed for the dilithium
salts requires two magnetically inequivalent subunits, suggest-
ing that the disodium salt is fundamentally different. Second,
there are two aging effects deriving from slow aggregate
equilibrations, one quite subtle and of unknown consequence
(discussed in the context of MCV below) and the other more
striking and consequential.
The incomplete conversions are part of a complex story
described below, but preliminary comment is warranted here.
Before we appreciated the importance of temperature control,
we often recovered significant (20−30%) starting material,
which was baffling. We initially suspected competitive
dehydrohalogenations of the alkyl halides by the disodiated
enolate, but alkenes were not observed by NMR spectroscopy
or GC, provided that we took precautions to avoid residual
NaDA. In fact, the nearly instantaneous dehydrohalogena-
tion11c acts to quench excess NaDA, with the resulting alkene
being diagnostic of adequate titers. Efforts to force alkylations
in aged samples by raising the temperature afforded low levels
(<10%) of byproducts such as 10 and 11, deriving from O-
alkylation. O-Alkylation is particularly acute when NaDA is
replaced with NaHMDS, suggesting that reversible proton
transfer may somehow be involved. tert-Butyl bromoacetate
(entry 6) seemed particularly problematic; with this substrate,
control of both stoichiometry and temperature provided only
modest conversion and O-alkylated side products, with isolated
yields of the desired product in an erratic 20−50% range. The
potential acidity of tert-butyl bromoacetate reinforces suspi-
cions that reversible proton transfer is at play.16
In our first study of aging, samples of disodium enolate 8
1
were incrementally warmed and recooled. Subsequent H and
13C NMR spectra, recorded at −80 °C, showed no detectable
structural changes after warming to −20 °C, at which point an
irreversible change was observed (Figure 1). No further
changes are noted on warming to >20 °C. Qualitatively, the
spectral changes seemed to correlate with the emergence of
aging effects that caused the reduced (20−50%) conversions in
the alkylations. What is also notable from Figure 1C is that the
new species appears to have two components in an approximate
3:1 ratio. We must confess, however, that the aging is erratic,
varying considerably from sample to sample: Figure 1 is the
cleanest example of this aging effect and has proven difficult to
replicate. Systematic variations in the NaDA concentration
suggest that aging is more acute at lower NaDA titers. Although
the effect is real, we terminated efforts to understand it. Further
hints, however, are discussed below.
Solution Structure. The acute challenges of characterizing
dianions17 are exacerbated by the absence of M−O scalar
coupling to study aggregation and M−N scalar coupling to
probe Na−N contacts. (6Li−15N couplings were detected in
lithium enolate 2, for example.5) We used the method of
continuous variations (MCV)18 to determine the degree of
aggregation of disodium salt 8 and standard 2D-NMR
spectroscopies (COSY, HMBC, HSQC, NOESY, and
The use of MCV18 to determine the aggregation state of
unaged samples involves making binary mixtures of structurally
C
DOI: 10.1021/jacs.9b08176
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
distinct enolates of unknown aggregation state, n, to generate an
ensemble of homoaggregates (An and Bn) and heteroaggregates
(AxBn−x). The homo- and heteroaggregates could, in principle,
heteroaggregates. The two homoaggregates age to a fully
equilibrated ensemble of homo- and heteroaggregates with an
approximate half-life of 5 h at −78 °C. We have noted such
aging effects for many enolates.22 The time scale of this aging
effect is distinctly different from that of the aging effect
illustrated in Figure 1. We conclude that the concurrently
generated enolates form ensembles of aggregates in rational
proportions but under kinetic control. Accordingly, for the
purposes of the MCV analysis, substrates were added
concurrently, and the resulting ensembles were aged for 18−
24 h at −78 °C to ensure full equilibration.
1
be monitored using H, 13C, and 15N NMR spectroscopies;
13C{1H} NMR spectroscopy sufficed for our purposes. The
pairing partners must be sufficiently distinct to generate
ensembles with adequate spectral resolution but similar enough
to accurately reflect the aggregation states of the homoag-
gregates. We explored combinations of enolates 8 and 14−17
to generate homo- and heterochiral ensembles.
In the case of the octalithiated Myers enolates, heterochiral
pairs of the same enolate, such as scalemic mixtures of (R,R)-2
and (S,S)-2, gave us excellent resolution, yet afforded the wrong
answer owing to a high thermochemical preference for 2:1 and
1:2 hexalithiated heterochiral forms.5 To the best of our
knowledge, that is a unique failure among hundreds of such
MCV studies of lithium enolates. Mixtures of disodium salts
(R,R)-8 and (S,S)-8, by contrast, showed no evidence of
heteroaggregation whatsoever. Fortunately, mixtures of 8 with
structurally distinct enolates 14−17 in the homochiral (R,R)
series worked well.
Before discussing the MCV results, we must briefly describe a
second aging effect observable at −78 °C that would have gone
undetected had we not undertaken the MCV studies. In short,
we found that the method of enolization dictated the behavior
of the ensemble (Scheme 1). Thus, the simultaneous addition
Scheme 1. Aging of Sodiated Enolate Mixtures
Binary mixtures generated from 8 and 14−17 form
homochiral ensembles that are, without exception, consistent
with a structural model showing octasodiated tetramers. The
8−15 pair with Me and i-Pr substituents, respectively (Figure
2), showed the best resolution. All ensembles showed
homoaggregates manifesting a single magnetically distinct
subunit as noted for 8, a single isomeric form corresponding
to 3:1 and 1:3 heteroaggregates, and two or three (out of a
possible three) 2:2 heteroaggregates with the third isomer
resolving reluctantly. These symmetries are important, vide
infra. Plotting the relative concentrations of the homo- and
heteroaggregates versus measured23 mole fraction of dianionic
subunit 15 (XB) affords a Job plot fit to a tetramer-based model
(Figure 3).
of both enolate precursors (substrate A + substrate B in THF)
to NaDA to concurrently generate enolates 8 and 15 affords
ensembles of homo- and heteroaggregates that outwardly
appear normal (as exemplified in Figure 2). By contrast, the
sequential addition of the enolate precursors to NaDA, with
adequate delay to separate the enolizations and aggregations
temporally, affords homoaggregates to the near exclusion of
2D-NMR spectra recorded on unaged samples of 8 show a
single magnetically discrete subunit (Figure 4). The phenyl
Figure 2. Partial 13C{1H} NMR spectra of solutions of disodium enolates (R,R)-8 (A) and (R,R)-15 (B; 0.25 M total concentration) in neat THF at
−80 °C. Samples were maintained at −80 °C for 18−24 h to equilibrate the ensembles.
D
DOI: 10.1021/jacs.9b08176
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
metry allowed us to show that the four magnetically distinct
subunits contained phenyl moieties on the concave face, as
drawn in Figure 4. The correlations (see Supporting
Information) are fully consistent with 3:1 heteroaggregate 18
(Figure 5), which, in turn, supported the assignment of the
homoaggregate of 8 as homotetramer 19.
The octagonal prismatic structure of 19 with four THF
ligands coordinated to the sodiums that do not have Na−N
contacts was computationally viable. If, however, four THF
ligands are placed on the proximal sodiums to generate a
tetrasolvate with N−Na−THF connectivity, the aggregate
collapses to stacked cube (20, Figure 5).24 Although it seems
less intuitive (to us at least) to solvate the sodium already
bearing a nitrogen-based ligand, 20 is calculated to be 13 kcal/
mol more stable than 19. Aggregate 20 shows the same
symmetry and is fully consistent with the spectroscopic data.
Although we do not view the computations as the definitive
answer, we will refer to the tetramer as 20 from this point
forward.
A potential alternative homotetramer, 21, displays the same
high symmetry as 20 and is computationally preferred by 3
kcal/mol relative to 20. In contrast to 20 with the enolate
oxygens on the top and bottom faces of the stack, stacked cube
21 places the enolate oxygens in the internal positions.
However, 21 (as well as the corresponding octagonal prismatic
form) is missing critical spatial relationships observed
spectroscopically.
Figure 3. Job plot showing the relative integrations of octasodiated
homoaggregates (A4 and B4) and heteroaggregates (A3B, A2B2, and
AB3) versus measured mole fractions23 of (R,R)-15 (XB) for 0.25 M
mixtures of sodium enolates (R,R)-8 (A) and (R,R)-15 (B) in neat
THF at −80 °C. The curves result from a parametric fit to a tetramer
model.18b
X-ray Structure of Decomposition. A crystal grown by
fully aging a sample of enolate 8 at ambient temperatures
afforded the X-ray crystal structure of aggregate 22 shown in
Figure 6. Although the crystal structure of 22 is not what a
crystallographer would call publishable and offers no insights
into the solution structure of 8 in unaged samples, it does
contain several notable features. The aggregate is composed of
six dianionic subunits of 8 and two monoanionic alkoxides (23)
resulting from protonation of the enolate. The structure shows
a number of Na−N contacts akin to the Li−N contacts noted
for enolate 2 and supported computationally in Figure 6.
The structure in Figure 6 seemed spurious (a rogue) on first
inspection. Recall, however, that a warming solution of enolate
8 generates (albeit irreproducibly) a new species with
resonances in a 3:1 ratio (Figure 1C), as would be expected
for 22, and that alkylations of such aged samples suffer from
significantly reduced percent conversions (50−80%). Aggregate
22 and related decompositions occur in sealed tubes containing
no obvious proton source. Is it possible that aggregate 20
scavenges 2 equiv of diisopropylamine to regenerate NaDA (eq
4)? We are untroubled by the thermochemistry implicit in eq 4,
given that aggregate-based stabilizations can be considerable.
This hypothesized proton transfer from i-Pr2NH is vaguely
reminiscent of deuteration studies in which Seebach was forced
to invoke transitory proton transfers from the i-Pr2NH to an
enolate to explain failed deuterations.25 One control experiment
supports this hypothesis. Deuteration of an unaged sample of 8
with MeOD afforded 95% of the expected monodeuterated 1.
By contrast, a parallel sample of 8, prepared from the same
stock solutions, was aged for 90 min at 25 °C, and then
quenched with MeOD. In this reaction, 1 was recovered cleanly
but with only <10% deuteration.
Figure 4. A single magnetically distinct subunit of 8 showing selected
(important) intrasubunit correlations (red) and intersubunit correla-
tions (blue).
moiety displays five discrete protons, indicating restricted
rotation and evidencing low fluxionality. The Na−N contact
shown in Figure 4 is reasonable based on analogous Li−N
contacts in the dilithium salt 25 and was supported both
crystallographically and computationally (vide infra). The
challenge with any homoaggregated species, however, is
distinguishing between intra- and intersubunit correlations.
Correlation “a” in Figure 4 suggests the phenyl resides on the
concave face, but additional correlations, such as b−d, likely
result from intersubunit contacts from proximate magnetically
equivalent subunits. These ambiguities undermined our
confidence in a structural assignment.
We resolved the ambiguity presented by intra- versus
intersubunit correlations by leveraging the results from MCV.
A 6:1 mixture of enolates 8 and 15 contained the
homoaggregate of 8 along with low concentrations of a 3:1
heteroaggregate (18) with three magnetically inequivalent
subunits of 8 and a single subunit of 15. We successfully
resolved significant portions of all four subunits in the 3:1
heteroaggregate (Supporting Information). The broken sym-
20 + 2i‐Pr2NH → 22 + 2NaDA
(4)
Aging Effects: Lingering Concerns. Qualitatively, the
aging effects on structure correlate with reduced conversions in
E
DOI: 10.1021/jacs.9b08176
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Figure 5. Tetrameric aggregates of Myers enolates and partial structures of the computed forms.
the alkylation of enolate 8. Quantitatively, the alkylation seems
to be more sensitive to temperature than are the spectroscopi-
cally studied aggregate exchanges. We suspect that this
discrepancy arises from aging effects on the mixed aggregates
formed at partial conversion. This is a difficult assertion to
document. The fact that warming causes inferior alkylation also
suggests that aging is more temperature sensitive than is the
alkylation. A second quantitative discord comes from rate
studies (below) showing reversible deaggregation that seems
more facile than the formation of heteroaggregates in Scheme 1.
F
DOI: 10.1021/jacs.9b08176
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
practice, quenching samples shows that percent conversion in
the crude product correlates with the spectroscopic loss of 20.
Rate studies using the method of initial rates26 show a first-
order dependence on n-BuI (Figure 9), a third-order depend-
ence on THF (Figure 10), and, most critically, a 1/4-order
dependence on aggregate 20 (Figure 11).27 The natural log
version of Figure 11 is included as an inset.28 The idealized rate
law29 in eq 5 is consistent with the generic mechanism in eqs 6
and 7.30 The mechanism presumes that tetramer 20 has one
coordinated THF ligand per subunit, an assumption with
computational but no experimental support.
−d[20]/dt = k[20]1/4[n‐BuI][THF]3
(5)
1
4
(enolate)4(THF)4 + 3THF F enolate(THF)4
(6)
(7)
20
1
x
enolate(THF)4 + n‐BuI → (RONa)x + NaI
Although tetramer 20 foreshadows potential structural details
of a fleeting monomeric intermediate, the similarities would be
superficial. The resting state of the tetrasolvated monomers,
however, should share many structural features with the rate-
and product-determining transition structures. Figure 12 shows
the two most stable tetrasolvated monomers, 24 and 25, of
eight total. Before discussing the three critical variables that
required careful evaluation, we should mention a few that are
non-negotiable because only one option is viable.
Without fail, all eight computed tetrasolvated monomers
show an irresistible penchant to form a tight Na−N contact
(2.4−2.5 Å). An analogous contact was observed in the lithium
variants and is observed in crystal structures of simple lithium
carboxamide enolates by Williard and co-workers.31 A THF
bridging the sodium cations shown in Figure 12 was also
computationally unavoidable. Such bridging THFs are
documented crystallographically for both sodium32 and
lithium.33 We have also invoked them as potentially important
fleeting intermediates in deaggregations.34 The three η1-bound
(terminal) THF ligands are decidedly tetrahedral at oxygen,
unlike the trigonal planar geometries of lithium-bound THFs.
This differential preference was noted decades ago by Seebach
and Dunitz from a survey of the crystallographic database.35
The three important variables demanding our full attention
are as follows. First, a simple chair−chair flip interconverts
pseudodiequatorial substituents along the ethanolamine back-
bone with an Ar−C−C−Me torsional angle of 44−57° (see 24)
to a pseudodiaxial form with a torsional angle of 159−172° (see
25). Next, the phenyl moiety can reside either on the concave
(endo) face as in 24 or on the convex (exo) face as in 25. (As an
aside, the phenyl on the concave face is preferred in tetramer
20.) Last, the fourth THF can be placed either proximate to the
N−bound sodium (not shown) or on the seemingly more open
sodium, as shown in both 24 and 25. Oddly, these two most
stable structures share only one of three variables, the THF
placement. Even then, other reasonable structures have the
alternative placement. The eight isomers span a 9−10 kcal/mol
range.
Figure 6. X-ray structure of 22 containing six dianions corresponding
to 8 and two alkoxides corresponding to 23. THFs are omitted for
clarity.
In this case, reduced dissociation rates of the more sterically
demanding 15 would inhibit exchange with 8. We were unable
to design a satisfying experiment to investigate the intersubunit
exchange using only enolate 8.
Rate Studies and Mechanism. Monitoring the alkylation
1
of 0.10 M 8 with 0.40 M n-BuI in neat THF-d8 by H NMR
spectroscopy shows an initial burst of 1-butene owing to
instantaneous E2-elimination by the slight excess of NaDA,
which confirms adequate titer and serves as an internal
standard. The slow loss of 8 (aggregate 20) and formation of
new products (Figure 7) is surprisingly clean given how
complex the spectra could have been owing to intervening
mixed aggregates. Although we suspected the new species may
be the alkoxide of product 9 (R = n-Bu), metalation of 9 with
1.0 equiv of NaDA to generate an authentic sample afforded
complex resonances. (Of course, such control experiments are
difficult to interpret without understanding the aging of the
alkoxide.) Plotting the disappearance of tetramer 20 over time
reveals a decay that, while necessarily neither first nor second
order (Figure 8), shows no significant evidence of auto-
inhibition or autocatalysis. Alkylations of samples spiked with
highly soluble NaI show no measurable rate effects. In theory,
tetramer 20 could be fully consumed at low (25%) conversion
and replaced by new, altogether different mixed aggregates
retaining multiple dianionic and monoanionic subunits. In
Of course, the selectivities are dictated by the competing
transition states (modeled with EtBr). The transition states are
subject to all of the vicissitudes found in the monomeric resting
states discussed above and several unique to the transition
structures. The orientation of the methyl moiety of EtBr is non-
G
DOI: 10.1021/jacs.9b08176
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
1
Figure 7. H NMR spectra following the alkylation of 8 (0.10 M) with n-BuI (0.40 M) in neat THF-d8 at −60 °C with formation of an
uncharacterized product (*).
Figure 10. Plot of initial rate versus THF-d8 concentration for
alkylation of 0.050 M 8 and 0.20 M n-BuI in hexanes cosolvent at −80
°C. The curve depicts an unweighted least-squares fit to the function
f(x) = axn such that a = (1 2) × 10−6, n = 3.0 0.9.
Figure 8. Decay of dianion 8 (0.10 M) with n-BuI (0.40 M) in neat
THF-d8 at −60 °C as shown in Figure 7.
negotiable; one rotamer is markedly preferred over the other
two. The EtBr can approach the concave (endo) or convex
(exo) face but invariably with Na−Br contacts. Exo approach is
accompanied by a Na−Br contact proximate to the Na−N
contact, whereas endo approach shows a Na−Br contact on the
sodium distal to the nitrogen. Figure 13 illustrates the two
lowest energy transition structures (of 16 total) leading to the
major product (26) and minor product (27). The other 14
transition structures have been archived in the Supporting
Information. Transition structures 26 and 27 also correspond
to approach of the EtBr to the endo and exo faces, respectively.
Intrinsic reaction coordinate (IRC) calculations36 on 26 and 27
afford first-formed minima with marked lengthening of the Na−
N bonds and only marginal additional shortening of the Na−Br
bonds.
Figure 9. Plot of initial rate versus n-BuI concentration for alkylation
of 0.10 M 8 in neat THF-d8 at −80 °C. The curve depicts an
unweighted least-squares fit to the function f(x) = axn such that a = (3
1) × 10−3, n = 0.97 0.08.
H
DOI: 10.1021/jacs.9b08176
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
prediction. Examining other basis sets similarly afforded no
consequential differences, only interesting philosophical ques-
tions discussed below. We even considered the possibility that
the THF order in Figure 10 is misleading and probed the
trisolvated monomers (Supporting Information), but they
offered no relief from the cunundrum.
Largely for entertainment value, we created a composite of
the ideal transition state by averaging the contributions of the
four variables independently. The 16 transition states offer four
sets of eight binary pairs in which only one variable has been
changed. Accordingly, on average the preferred orientations
include pseudodiequatorial substituents on the ethanolamine
backbone (−1.2 4.3 kcal/mol), disolvation distal from the
Na−N contact (−1.2 4.4 kcal/mol), placement of the phenyl
moiety on the convex face and methyl on the concave face
(−0.8 2.4 kcal/mol), and exo approach of EtBr (−0.6 5.9
kcal/mol). The near thermoneutral preferences and large error
bars aside, this statistical composite (28, Figure 14) with each
Figure 11. Plot of initial rate versus enolate 8 concentration for
alkylation of 8 with 0.49 M n-BuI in neat THF-d8 at −80 °C. The
asterisk (*) denotes a point at 0.025 M enolate in which poor signal-to-
noise rendered it unreliable. The curve depicts an unweighted least-
squares fit to the function f(x) = axn such that a = (3.9 0.1) × 10−3, n
= 0.29 0.01. The inset shows the log(initial rate) versus log[enolate].
The curve depicts an unweighted least-squares fit to the function f(x) =
ax+b such that a = 2.40 0.01, b = 0.29 0.01.
Figure 14. Statistical composite transition structure 28 defined by
control of four key variables in their preferred modes.
variable in the preferred orientation, while not the most stable
transition structure of the 16 transition structures considered,
predicts the major alkylation product. This thought experiment
is provocative but should not be taken too seriously.
Figure 12. Two most stable resting states for tetrasolvated monomeric
enolate 8 with relative energies. η1 THFs are omitted for clarity.
The above discussion underscores some deeply philosophical
issues. Several decades of exploring computational chemistry
within the confines of organolithium chemistry have revealed
many details that we were not savvy enough to anticipate. Such
computational discoveries forcibly remove some human bias.
Bridging THF ligands and Li−N/Na−N contacts foisted upon
us during studies of Myers enolates are emblematic. Suppose,
however, that shopping for basis sets had revealed one that
replicated the selectivity that we already knew from experiment.
Should we simply use that basis set? Is this really proper
scientific method? In the isolated world of one case study and
from investigators who are, relatively speaking, Luddites
computationally, we do not think so. Such an observation
would, however, prompt us to try that basis set again in future
case studies. Should superior experiment−theory correlations
from that basis set persist, then the beginnings of an important
trend have emerged.
The synergies of experimental and computational data are
critical. By using both, we are examining the efficacy of the
computations as much as computationally probing structure
and mechanism. Failed theory−experiment correlations prompt
us to question both the theory and the experiment. Is it a
problem with the basis set, the THF order, or user error? One
should not underestimate the sensitivity of the computational
results to the user’s willingness to probe alternatives and the
Figure 13. Two most stable transition structures for tetrasolvated
monomer-based alkylations with ethyl bromide leading to the
experimentally observed major product (26) and minor product
(27) with relative energies.
Transition structures 26 and 27 in Figure 13 include one
more niggling detail: they predict the wrong stereochemistry by
0.7 kcal/mol. This is not a shocking failure and could be argued
to be within the propagated error of the calculations given the
number of variables involved. Probes for potential problems
included single point calculations on 26 and 27 with the η1-
bound THFs removed or with the methyls and phenyls along
the ethanolamine backbone replaced by 1.11 Å C−H bonds.
Neither probe revealed an obvious source of the failed
I
DOI: 10.1021/jacs.9b08176
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
structural and mechanistic studies was prepared as a white crystalline
solid as described previously11a and manipulated using a standard
glovebox, vacuum line, and syringe techniques. The benchtop
procedures used no specialized inert atmosphere equipment as
described below. Myers enolate precursors were either purchased or
prepared as described previously.1
incursion of confirmation bias. We wonder whether computa-
tional data in the absence of supporting mechanistic data should
be referred to as elucidating a mechanism or merely examining
it. With that said, we submit that as the computational
community improves its methods, the broader organic
chemistry community benefits from bringing computations to
bear on experimental problems, even if these computations are
not done with the greatest skill or attention to detail. They
should be allowed to do so without fear of falling short of the
state-of-the-art standards. It has been said by physician Howard
Skipper that “a model is a lie that helps you see the truth.”
NMR Spectroscopy. Stock solutions of NaDA/THF were
prepared at −78 °C and held at this temperature until spectra were
recorded. An NMR tube under vacuum was flame-dried on a Schlenk
line and allowed to return to room temperature. It was then backfilled
with argon and placed in a dry ice/acetone bath at −78 °C. The
appropriate amounts of acylated pseudoephedrine and NaDA (2.5
equiv) were added sequentially via syringe. The tube was sealed under
partial vacuum and vortexed three times on a vortex mixer for 5 s.
Samples could be stored for up to 2 weeks in a freezer at −86 °C. Each
sample typically contained 0.25 M total enolate titer generated using
CONCLUSIONS
■
The alkylations of disodiated Myers enolates provide results
that are largely comparable to those obtained by Myers using
dilithiated enolate 2/LiCl mixtures. The disodium salts have the
advantage that they do not require additives and, consequently,
can be effected at high concentrations preferred for industrial
scales. There are, however, offsetting costs. Alkylations of the
disodium salts require more rigorous temperature control to
prevent aging and O-alkylations, and several electrophiles
simply did not react well.
1
0.63 M NaDA (0.13 M excess). Standard H and 13C NMR spectra
were recorded on a 500 MHz spectrometer at 499.92 and 73.57 MHz,
respectively. 13C resonances are referenced to the CH2O resonance of
THF at −80 °C (67.57 ppm). Two-dimensional NMR spectroscopies
(COSY, HMBC, HSQC, NOESY, and ROESY) were recorded using
standard pulse sequences.
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 a stock solution of enolate 8
in neat THF. The vessel was cooled to −78 °C in a dry ice bath
prepared using fresh acetone. After a background spectrum was
recorded, neat alkyl halide was added with stirring. IR spectra were
recorded every 6 s with monitoring of the absorbance at 1620 cm−1
over the course of the reaction.
The aging effects remind us that many who use enolates likely
do not understand how robust enolate aggregates can be.
Aggregate exchanges can be so slow that equilibration requires
warming to ambient temperatures.22 Any effort to optimize the
chemistry of alkali metal enolates must respect the complexity
that this phenomenon imposes. In a study reported two decades
ago, Merck investigators found that an aging step was critical to
success.37 Myers bypassed a highly problematic aging by adding
5 equiv of LiCl, but even then, the procedure required warming
to ambient temperatures to form the requisite dilithiated
enolate−LiCl adduct. In the case of disodium Myers enolates,
aging is a destructive process in which the enolization appears
to be pushed in reverse to produce unenolized alkoxide. Of
course, every enolate−solvent combination is unique, but it
seems likely that synthetic chemists are getting whipsawed by
such aging effects without realizing it.
The results of the disodium salt alkylations cause us to reflect
on the mechanistic studies of the dilithium Myers enolates. Our
failure to assign the structure of the key LiCl adduct of enolate 8
left us with three mechanistic possibilities, including one in
which the LiCl adduct was suggested to be a fluctional source of
the LiCl-free monomer. Given the monomer-based alkylation
of the disodium salt, the analogous monomer-based mechanism
for the dilithium salt gains credibility. Some of the details of the
computational data from that study show parallels, including a
Li−Br contact and bridging THF.5
Going forward, several issues remain to be resolved. The
obvious next move is to explore both dilithium and disodium
salts of the diphenyl-substituted second-generation enolates
derived from 3. It should be much easier now. Taking a more
expanded view, the protocols to probe Myers enolates should
translate to other synthetically important dianions used
routinely in organic synthesis.17,38 Last, unraveling the
structure−reactivity relationships of disodium Myers enolates
represents progress toward understanding and further devel-
oping organosodium chemistry to pique the interest of those
who use alkali metal-based reagents.
MCV. The mathematical treatment for creating Job plots using
Matlab has been described in detail previously.18b
Representative NaDA Preparation. Sodium slices (600 mg) cut
from sodium cubes were placed in a 50 mL pear-shaped flask. Dry
THF (5.0 mL) and technical-grade diisopropylamine (3.0 mL, 21
mmol) were added to the flask under positive argon pressure, and the
mixture was maintained at 20 °C. Isoprene (1.0 mL, 10 mmol) was
added at 0 °C all at once. Stirring for 45 min yielded a brown-yellow
solution. Darkening of the sodium surface appears to correlate with the
completion of the reaction. The solution is readily decanted by syringe
from with unreacted sodium slices and should be done so promptly
(<2 h) to prevent gelling. The resulting yellow-brown solution should
be used within 5 h if stored at 0 °C or within 48 h if stored at −20 °C.
(Warming to 0 °C makes handling the viscous solution easier.)
Titration15 routinely affords 80−90% of the anticipated normality
(1.6−1.8 M). A 10-fold scale-up (200 mmol) afforded analogous
results without a measurable exotherm. Monitoring the internal
reaction temperatures on larger scale reactions is advised. The spent
sodium is quenched by adding sequentially adding hexane followed by
isopropanol dropwise.
Representative Alkylation with n-BuI. 100 mg (0.45 mmol) of
1 was added to a flame-dried 5 mL pear shaped flask equipped with a
T-joint and a magnetic stir bar under argon and cooled to −78 °C.
NaDA in THF solution (800 μL, 1.41 M, 1.13 mmol) was added. The
mixture was stirred at −78 °C for 20 min until substrate 1 dissolved. n-
BuI (100 μL, 0.87 mmol, 1.9 equiv) was added to the solution and
stirred at −78 °C for 6 h (or −40 °C for 1 h). The reaction was
quenched with saturated NH4Cl (0.50 mL), and the resulting biphasic
mixture was partitioned between water (0.50 mL) and ethyl acetate
(10 mL). The aqueous layer was separated and extracted further with
three 5 mL portions of ethyl acetate. The combined organic layers
were dried over anhydrous magnesium sulfate, filtered, and then
concentrated. Purification of the residue by flash column chromatog-
raphy (50% ethyl acetate in hexanes) afforded 103 mg (82%) of
EXPERIMENTAL SECTION
Reagents and Solvents. THF and hexane were distilled from
solutions containing sodium benzophenone ketyl. NaDA used for
■
J
DOI: 10.1021/jacs.9b08176
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
product as a white crystalline solid whose spectral properties were
found to be in accordance with those previously reported.1a
(5) Zhou, Y.; Jermaks, J.; Keresztes, I.; MacMillan, S. N.; Collum, D.
B. Pseudoephedrine-Derived Myers Enolates: Structures and Influence
of Lithium Chloride on Reactivity and Mechanism. J. Am. Chem. Soc.
2019, 141, 5444.
(6) Johnson, N. W. Convex Solids with Regular Faces. Can. J. Math.
1966, 18, 169.
(7) Investigators at Merck carried out a facile Michael addition to a
highly stabilized arene-substituted Myers dianion generated using
LiHMDS in TMEDA/THF without added lithium salts. Added LiCl
reverses the stereoselectivity. (a) Smitrovich, J. H.; Boice, G. N.; Qu,
C.; DiMichele, L.; Nelson, T. D.; Huffman, M. A.; Murry, J.;
McNamara, J.; Reider, P. J. Pseudoephedrine as a Chiral Auxiliary for
Asymmetric Michael Reactions: Synthesis of 3-Aryl-δ-lactones. Org.
Lett. 2002, 4, 1963. (b) Smitrovich, J. H.; DiMichele, L.; Qu, C.; Boice,
G. N.; Nelson, T. D.; Huffman, M. A.; Murry, J. Michael Reactions of
Pseudoephedrine Amide Enolates: Effect of LiCl on Syn/Anti
Selectivity. J. Org. Chem. 2004, 69, 1903.
Representative Kinetic Reaction. A representative reaction was
carried out as follows: an NMR tube equipped with double septa was
charged with 0.15 M 1 in THF-d8 (400 μL) and 0.75 M NaDA in
THF-d8 (200 μL). The sample was vortexed three times on a vortex
mixer for 5 s with cooling between each vortexing. To this solution was
1
added n-BuI. H NMR spectra were recorded at −80 °C at 1.0 min
intervals.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.9b08176.
Spectroscopic, crystallographic, computational, rate, and
MCV data (PDF)
(8) Sarabu, R.; Bizzarro, F. T.; Corbett, W. L.; Dvorozniak, M. T.;
Geng, W.; Grippo, J. F.; Haynes, N.-E.; Hutchings, S.; Garofalo, L.;
Guertin, K. R.; Hilliard, D. W.; Kabat, M.; Kester, R. F.; Ka, W.; Liang,
A.; Mahaney, P. E.; Marcus, L.; Matschinsky, F. M.; Moore, D.; Racha,
J.; Radinov, R.; Ren, Y.; Qi, L.; Pignatello, M.; Spence, C. L.; Steele, T.;
Tengi, J.; Grimsby, J. Discovery of PiragliatinFirst Glucokinase
Activator Studied in Type 2 Diabetic Patients. J. Med. Chem. 2012, 55,
7021.
(9) (a) Seebach, D. Structure and Reactivity of Lithium Enolates.
From Pinacolone to Selective C-Alkylations of Peptides. Difficulties
and Opportunities Afforded by Complex Structures. Angew. Chem., Int.
Ed. Engl. 1988, 27, 1624. (b) Braun, M. Lithium Enolates: ‘Capricious’
Structures - Reliable Reagents for Synthesis. Helv. Chim. Acta 2015, 98,
1.
(10) Leading references to organosodium chemistry: (a) Mulvey, R.
E.; Robertson, S. D. Synthetically Important Alkali-Metal Utility
Amides: Lithium, Sodium, and Potassium Hexamethyldisilazides,
Diisopropylamides, and Tetramethylpiperidides. Angew. Chem., Int. Ed.
2013, 52, 11470. (b) Seyferth, D. Alkyl and Aryl Derivatives of the
Alkali Metals: Useful Synthetic Reagents as Strong Bases and Potent
Nucleophiles. 1. Conversion of Organic Halides to Organoalkali-Metal
Compounds. Organometallics 2006, 25, 2. (c) Seyferth, D. Alkyl and
Aryl Derivatives of the Alkali Metals: Strong Bases and Reactive
Nucleophiles. 2. Wilhelm Schlenk’s Organoalkali-Metal Chemistry.
The Metal Displacement and the Transmetalation Reactions. Metal-
ation of Weakly Acidic Hydrocarbons. Superbases. Organometallics
2009, 28, 2. (d) Benkeser, R. A.; Foster, D. J.; Sauve, D. M.; Nobis, J. F.
Metalations With Organosodium Compounds. Chem. Rev. 1957, 57,
867.
AUTHOR INFORMATION
Corresponding Author
*dbc6@cornell.edu
ORCID
Samantha N. MacMillan: 0000-0001-6516-1823
David B. Collum: 0000-0001-6065-1655
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Institutes of Health (GM131713) for
support.
REFERENCES
■
(1) (a) Myers, A. G.; Yang, B. H.; Chen, H.; Gleason, J. L. Use of
Pseudoephedrine as a Practical Chiral Auxiliary for Asymmetric
Synthesis. J. Am. Chem. Soc. 1994, 116, 9361. (b) Myers, A. G.;
McKinstry, L. Practical Syntheses of Enantiomerically Enriched γ-
Lactones and γ-Hydroxy Ketones by the Alkylation of Pseudoephe-
drine Amides with Epoxides and their Derivatives. J. Org. Chem. 1996,
61, 2428. (c) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.;
Kopecky, D. J.; Gleason, J. L. Pseudoephedrine as a Practical Chiral
Auxiliary for the Synthesis of Highly Enantiomerically Enriched
Carboxylic Acids, Alcohols, Aldehydes, and Ketones. J. Am. Chem. Soc.
1997, 119, 6496.
(11) (a) Ma, Y.; Algera, R. F.; Collum, D. B. Sodium
Diisopropylamide in N,N-Dimethylethylamine: Reactivity, Selectivity,
and Synthetic Utility. J. Org. Chem. 2016, 81, 11312. (b) Algera, R. F.;
Ma, Y.; Collum, D. B. Sodium Diisopropylamide: Aggregation,
Solvation, and Stability. J. Am. Chem. Soc. 2017, 139, 7921. (c) Ma,
Y.; Algera, R. F.; Woltornist, R. A.; Collum, D. B. Sodium
Diisopropylamide-Mediated Dehydrohalogenations: Influence of
Primary- and Secondary-Shell Solvation. J. Org. Chem. 2019, 84, ASAP.
(12) Barr, D.; Dawson, A. J.; Wakefield, B. J. A Simple, High-Yielding
Preparation of Sodium Diisopropylamide and Other Sodium
Dialkylamides. J. Chem. Soc., Chem. Commun. 1992, 204.
(2) Evans, D. A.; Takacs, J. M. Enantioselective Alkylation of Chiral
Enolates. Tetrahedron Lett. 1980, 21, 4233.
(3) (a) Mellem, K. T.; Myers, A. G. A Simple, Scalable Synthetic
Route to (+)- and (−)-Pseudoephenamine. Org. Lett. 2013, 15, 5594.
(b) Morales, M. R.; Mellem, K. T.; Myers, A. G. Pseudoephenamine: A
Practical Chiral Auxiliary for Asymmetric Synthesis. Angew. Chem., Int.
Ed. 2012, 51, 4568. (c) Hogan, P. C.; Chen, C.-L.; Mulvihill, K. M.;
Lawrence, J. F.; Moorhead, E.; Rickmeier, J.; Myers, A. G. Large-scale
Preparation of Key Building Blocks for the Manufacture of Fully
Synthetic Macrolide Antibiotics. J. Antibiot. 2018, 71, 318.
̈
(4) (a) Sandham, D. A.; Taylor, R. J.; Carey, J. S.; Fassler, A. A
̌
(13) (a) Lochmann, L.; Pospísil, J.; Lím, D. On the Interaction of
Convergent Synthesis of the Renin Inhibitor CGP60536B. Tetrahedron
Lett. 2000, 41, 10091. (b) Dragovich, P. S.; Prins, T. J.; Zhou, R.
Formal, Stereoselective Synthesis of Hydroxyethylene Dipeptide
Isosteres Utilizing Pseudoephedrine Amides. J. Org. Chem. 1997, 62,
7872. (c) Sinz, C.; Bittner, A.; Brady, E.; Candelore, M.; Dallas-Yang,
Q.; Ding, V.; Jiang, G.; Lin, Z.; Qureshi, S.; Salituro, G.; Saperstein, R.
Discovery of N-Aryl-2-Acylindole Human Glucagon Receptor
Antagonists. Bioorg. Med. Chem. Lett. 2011, 21, 7124. (d) Narasimhulu,
C. P.; Das, P. Stereoselective Preparation of C1-C10 and C11-O14
Fragments of Narbonolide: Exploiting the Versatility of Thiazolidine-
thione Chiral Auxiliary. Synthesis 2009, 2009, 474.
Organolithium Compounds with Sodium and Potassium Alkoxides. A
New Method for the Synthesis of Organosodium and Organo-
potassium Compounds. Tetrahedron Lett. 1966, 7, 257. (b) Lochmann,
L.; Janata, M. 50 Years of Superbases Made from Organolithium
Compounds and Heavier Alkali Metal Alkoxides. Cent. Eur. J. Chem.
2014, 12, 537. (c) Lochmann, L.; Trekoval, J. Interactions of
Alkoxides: XI. Reactions of Substituted N-Lithium Amides with
Heavier Alkali Metal Alkoxides. a Novel Method for the Preparation of
N-Sodium and N-Potassium Dialkylamides. J. Organomet. Chem. 1979,
179, 123.
K
DOI: 10.1021/jacs.9b08176
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
(14) Because of the second-order THF dependence and one-half-
order NaDA dependence on the NaDA-mediated decomposition in
THF, high concentrations of NaDA in THF should on a percentage
basis decompose marginally more slowly.
(15) Kofron, W. G.; Baclawski, L. M. A Convenient Method for
Estimation of Alkyllithium Concentrations. J. Org. Chem. 1976, 41,
1879.
(16) We cannot rule out the possibility that the C- and O-alkylation
products from BrCH2COO-t-Bu stem from enolization and attack on a
transiently formed carbene. In fact, sequential addition of
BrCH2COO-t-Bu followed by pseudoephedrine amide 1 to excess
NaDA afforded a seemingly similar product distribution.
(26) Casado, J.; Lopez-Quintela, M. A.; Lorenzo-Barral, F. M. The
Initial Rate Method in Chemical Kinetics: Evaluation and
Experimental Illustration. J. Chem. Educ. 1986, 63, 450.
(27) The rate law provides the stoichiometry of the transition
structure relative to that of the reactants: The rate law provides the
stoichiometry of the transition structure relative to that of the
reactants: Edwards, J. O.; Greene, E. F.; Ross, J. From Stoichiometry
and Rate Law to Mechanism. J. Chem. Educ. 1968, 45, 381.
(28) Semilog plots, although often visually retrievable, can hide
subtleties such as nonzero intercepts and impose inadvertent nonlinear
weighting of the data.
(29) We define the idealized rate law as that obtained by rounding
the observed reaction orders to the nearest rational order.
(30) A number of general-purpose reviews on determining reaction
mechanism: (a) Meek, S. J.; Pitman, C. L.; Miller, A. J. M. Deducing
Reaction Mechanism: A Guide for Students, Researchers, and
Instructors. J. Chem. Educ. 2016, 93, 275. (b) Simmons, E. M.;
Hartwig, J. F. On the Interpretation of Deuterium Kinetic Isotope
Effects in C-H Bond Functionalizations by Transition Metal
Complexes. Angew. Chem., Int. Ed. 2012, 51, 3066. (c) Collum, D.
B.; McNeil, A. J.; Ramírez, A. Lithium Diisopropylamide: Solution
Kinetics and Implications for Organic Synthesis. Angew. Chem., Int. Ed.
2007, 46, 3002. (d) Algera, R. F.; Gupta, L.; Hoepker, A. C.; Liang, J.;
Ma, Y.; Singh, K. J.; Collum, D. B. Lithium Diisopropylamide: Non-
Equilibrium Kinetics and Lessons Learned about Rate Limitation. J.
Org. Chem. 2017, 82, 4513.
(17) Langer, P.; Freiberg, W. Cyclization Reactions of Dianions in
Organic Synthesis. Chem. Rev. 2004, 104, 4125.
(18) (a) Renny, J. S.; Tomasevich, L. L.; Tallmadge, E. H.; Collum,
D. B. Method of Continuous Variations: Applications of Job Plots to
the Study of Molecular Associations in Organometallic Chemistry.
Angew. Chem., Int. Ed. 2013, 52, 11998. (b) Liou, L. R.; McNeil, A. J.;
Ramírez, A.; Toombes, G. E. S.; Gruver, J. M.; Collum, D. B. Lithium
Enolates of Simple Ketones: Structure Determination Using the
Method of Continuous Variation. J. Am. Chem. Soc. 2008, 130, 4859.
(19) (a) Friebolin, H. Basic One- and Two-Dimensional NMR
Spectroscopy; Wiley VCH: Weinheim, 2010. (b) Claridge, T. D. W.
High-Resolution NMR Techniques in Organic Chemistry, 2nd ed.;
Elsevier: Amsterdam, 2009.
(20) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A.,
Jr.; Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels,
A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.;
Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford,
S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.;
Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.;
Cioslowski, J.; Ortiz, J. V.; Baboul, A. G.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.;
Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Gill, A.;
Nanayakkara, C.; Gonzalez, M.; Challacombe, P. M. W.; Johnson, B.;
Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.; Head-Gordon,
M.; Replogle, E. S.; Pople, J. A. Gaussian 09, revision A.02; Gaussian,
Inc.: Wallingford, CT, 2009.
(21) Zhao, Y.; Truhlar, D. G. The M06 Suite of Density Functionals
for Main Group Thermochemistry, Thermochemical Kinetics, Non-
covalent Interactions, Excited States, and Transition Elements: Two
New Functionals and Systematic Testing of Four M06-Class
Functionals and 12 Other Functionals. Theor. Chem. Acc. 2008, 120,
215.
(31) Williard, P. G. unpublished.
(32) (a) Rong, Y.; Palmer, J. H.; Parkin, G. Benzannulated tris(2-
Mercapto-1-imidazolyl)-hydroborato Ligands: Tetradentate κ4-S3H
Binding and Access to Monomeric Monovalent Thallium in an [S3]
Coordination Environment. Dalton Trans 2014, 43, 1397. (b) Peng,
H.; Zhang, Z.; Qi, R.; Yao, Y.; Zhang, Y.; Shen, Q.; Cheng, Y.
Synthesis, Reactivity, and Characterization of Sodium and Rare-Earth
Metal Complexes Bearing a Dianionic N-Aryloxo-Functionalized r-
Ketoiminate Ligand. Inorg. Chem. 2008, 47, 9828. (c) Bachmann, J.;
Hodgkiss, J. M.; Young, E. R.; Nocera, D. G. Ground- and Excited-
State Reactivity of Iron Porphyrinogens. Inorg. Chem. 2007, 46, 607.
(33) Representative examples of structurally characterized bridging
THF ligands: (a) Chivers, T.; Fedorchuk, C.; Parvez, M. Synthetic and
Structural Investigations of Monomeric Dilithium Boraamidinates and
Bidentate NBNCN Ligands with Bulky N-Bonded Groups. Inorg.
Chem. 2004, 43, 2643. (b) Briand, G. G.; Chivers, T.; Parvez, M. A
Novel Route to Chalcogenides of Heavy Pnicogens: Synthesis and X-
ray Structure of {(THF)3Li2[PhAs(Se)(NBut)2]}. J. Chem. Soc., Dalton
Trans. 2002, 3785.
(34) Hoepker, A. C.; Collum, D. B. Computational Studies of
Lithium Diisopropylamide Deaggregation. J. Org. Chem. 2011, 76,
7985.
(35) Chakrabarti, P.; Dunitz, J. D. Directional Preferences of Ether
O-Atoms Towards Alkali and Alkaline Earth Cations. Helv. Chim. Acta
1982, 65, 1482.
(36) Intrinsic reaction coordinate (IRC) calculations are defined as
“the minimum energy reaction pathway (MERP) in mass-weighted
cartesian coordinates between the transition state of a reaction and its
reactants and products.” They show the minima preceding and
following transition state.
(22) For leading references to marked enolate aging effects, see ref 5.
(23) The intended mole fraction refers to the mole fraction based on
what was added to the samples. The measured mole fraction, the mole
fraction within only the ensemble of interest, eliminates the distorting
effects of impurities.
(24) For representative examples of crystallographically characterized
stacked cubes of sodium salts, see: (a) Balloch, L.; Drummond, A. M.;
́
García-Alvarez, P.; Graham, D. V.; Kennedy, A. R.; Klett, J.; Mulvey, R.
E.; O’Hara, C. T.; Rodger, P. J.; Rushworth, I. D. Structural Variations
Within Group 1 (Li- Cs)+(2, 2, 6, 6-Tetramethyl-1-piperidinyloxy)−
Complexes Made via Metallic Reduction of the Nitroxyl Radical. Inorg.
Chem. 2009, 48, 6934. (b) Boyle, T. J.; Velazquez, A. T.; Yonemoto, D.
T.; Alam, T. M.; Moore, C.; Rheingold, A. L. Synthesis and
Characterization of a Family of Solvated Sodium Aryloxide
Compounds. Inorg. Chim. Acta 2013, 405, 374. (c) Scherpf, T.;
Wirth, R.; Molitor, S.; Feichtner, K. S.; Gessner, V. H. Bridging the
Gap Between Bisylides and Methandiides: Isolation, Reactivity, and
Electronic Structure of an Yldiide. Angew. Chem., Int. Ed. 2015, 54,
8542.
(37) Grabowski, E. J. J. Reflections on Process Research−The Art of
Practical Organic Synthesis. In ACS Symposium Series, 870; Abdel-
Magid, A. F., Ragan, J. A., Eds.; American Chemical Society:
Washington, DC, 2004; Chapter 1, pp 1−21.
(38) For leading references to structural studies of dianions, see ref 5.
(25) Laube, T.; Dunitz, J. D.; Seebach, D. On the Interaction
between Lithium Enolates and Secondary Amines in Solution and in
the Crystal. Helv. Chim. Acta 1985, 68, 1373.
L
DOI: 10.1021/jacs.9b08176
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX