Pseudophedrine-Derived Myers Enolates: Structures and Influence of Lithium Chloride on Reactivity and Mechanism

Article abstract of DOI:10.1021/jacs.9b00328

The structures and reactivities of pseudoephedrine-derived dianionic Myers enolates are examined. A combination of NMR and IR spectroscopic, crystallographic, and computational data reveal that the homoaggregated dianions form octalithiated tetramers displaying S₄-symmetric Li₈O₈ cores and overall C₂ symmetry. Computational and isotopic labeling studies reveal strong N-Li contacts in the carboxamide enolate moiety. The method of continuous variations proves deceptive, as octalithiated tetrameric homoaggregates afford hexalithiated trimeric heteroaggregates. A lithium diisopropylamide-lithium enolate mixed aggregate is found to be a C₂-symmetric hexalithiated species incorporating two enolate dianions and two lithium diisopropylamide (LDA) subunits. Structural and rate studies show that lithium chloride has little effect on the dynamics of the enolate homoaggregates but forms adducts of unknown structure. Rate studies of alkylations indicate that the aging of the aggregates can have effects spanning orders of magnitude. The LiCl-enolate adduct dramatically accelerates the reaction but requires superstoichiometric quantities owing to putative autoinhibition. Efforts and progress toward eliminating the requisite large excess of LiCl are discussed.

Full text of DOI:10.1021/jacs.9b00328

Article
Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
pubs.acs.org/JACS
Pseudophedrine-Derived Myers Enolates: Structures and Influence
of Lithium Chloride on Reactivity and Mechanism
Yuhui Zhou, Janis Jermaks, 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: The structures and reactivities of pseudoephe-
drine-derived dianionic Myers enolates are examined. A
combination of NMR and IR spectroscopic, crystallographic,
and computational data reveal that the homoaggregated
dianions form octalithiated tetramers displaying S -symmetric Li O cores and overall C symmetry. Computational and
4
8
8
2
isotopic labeling studies reveal strong N−Li contacts in the carboxamide enolate moiety. The method of continuous variations
proves deceptive, as octalithiated tetrameric homoaggregates afford hexalithiated trimeric heteroaggregates. A lithium
diisopropylamide−lithium enolate mixed aggregate is found to be a C -symmetric hexalithiated species incorporating two
2
enolate dianions and two lithium diisopropylamide (LDA) subunits. Structural and rate studies show that lithium chloride has
little effect on the dynamics of the enolate homoaggregates but forms adducts of unknown structure. Rate studies of alkylations
indicate that the aging of the aggregates can have effects spanning orders of magnitude. The LiCl−enolate adduct dramatically
accelerates the reaction but requires superstoichiometric quantities owing to putative autoinhibition. Efforts and progress
toward eliminating the requisite large excess of LiCl are discussed.
INTRODUCTION
In 1994, Myers and co-workers reported that dianions of type
derived from acylated pseudoephedrines (1) undergo
functionalizations with a range of electrophiles in high yields
and selectivities (eq 1). The products are deprotected by
Understanding reactivity and selectivity in solutions teeming
with observable and fleeting species demands a sound
understanding of solution structure. Challenges to determining
the structures of Myers enolates promised to be especially
daunting: (1) possible aggregate topologies illustrated in Chart
■
2
1
1
are representative but are by no means a comprehensive
Chart 1. Selected Possible Topologies of Myers Enolates
facile hydrolysis that appears to benefit from anchimeric
assistance from the pendant hydroxy moiety noted previously
2
by Evans using pyrrolidinol-derived amides. A key observation
was that ≥5.0 equiv of LiCl was essential for optimal yields.
Although no direct evidence attests to the role of LiCl, an
artist’s rendition (3) was offered to illustrate the opposite
selectivities observed for alkyl halide and epoxides. Despite the
need for large quantities of LiCl, which has the effect of
imposing concentration limits, the alkylations have found
applications in a number of pharmaceutical-scale drug
3
syntheses. They are now part of the pantheon of methods
used for asymmetric synthesis, and they display special value in
generating quaternary centers in exceptional yields and
selectivities.
Received: January 10, 2019
1
©
XXXX American Chemical Society
A
DOI: 10.1021/jacs.9b00328
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4
compilation of possible structural motifs; (2) positional
Chart 2. Structurally Characterized Homo- and
isomerism represented generically in eq 2 would amplify
Heteroaggregates and Mixed Aggregates (4−6) of Myers
Enolates
spectral complexity; (3) the difficulty of characterizing
5
dianions is exacerbated by the absence of observable scalar
Li−O coupling.
We describe herein studies of the structure and reactivity of
Myers enolates. We take unusual care to illustrate some of the
trials and tribulationsthe often unstated pain and suffering
en route to the answerwhile trying not to make the reader
suffer proportionately. The story is one of tactics and
strategies. Although we characterized several heteroaggregates
and a lithium diisopropylamide (LDA)−enolate mixed
aggregate spectroscopically (vide infra), our best efforts to
understand the all-important homoaggregate of 2 left us with
too many possible structures and too many niggling details that
simply did not afford an unapologetic assignment. A low-
resolution crystal structure that would be unpublishable in
isolation provided us the answer key, the Rosetta stone. The
crystallographic and spectroscopic data proved fully self-
consistent. Which structure of the many under consideration
was correct? In a word, none. We had many of the details right
but missed the topology of the Li O core that was, ironically,
8
8
6
lurking in the Cambridge Structural Database.
Dropping any pretense of presenting the data to the reader
and then making the assignment, we provide the plot-spoiling
solution structure of Myers enolate 2 as C -symmetric
2
octalithiated prism 4 constituted from four dianionic subunits
manifesting an S -symmetric core and overall C symmetry
polygonal prisms. The nonspecialist will find an adequate
survey of the results in the Discussion.
4
2
(Chart 2). The four N−Li contacts were foreshadowed
Substrates. Acylated pseudoephedrine-based enolates 2
computationally. Although four coordinated THF ligands are
omitted for clarity, they were the subject of considerable
experimental focus. As part of our efforts to use the method of
continuous variations (MCV), a favorite of ours for studying
1
and 7−22 (Chart 3) were prepared using standard protocols.
Chart 3. Myers Enolates
7
solution structures of enolates, we generated and charac-
terized heteroaggregates containing subunits of opposite
absolute configuration (heterochiral) that afforded hexalithi-
ated prisms of type 5. In short, MCV failed to provide
heteroaggregates that attest to the structures of the
homoaggregates. Control experiments to understand the
consequences of excess LDA revealed C -symmetric hexali-
2
[15
N](R,R)-2 and [ N](S,S)-2 to probe N−Li contacts
15
thiated mixed aggregate 6 (comprising two LDA subunits and
two dianionic subunits), which bears little relationship to the
enolate homoaggregates but shares several unusual features
with heteroaggregate 5. Rate studies of alkylations showed
1
5
originated from [ N]NH Cl, as shown in Scheme 1.
4
6
6
15
9
[
Li]LDA and [ Li, N]LDA were isolated as LiCl-free solids.
Solvation was probed in several ways, including by using
pyridine as a Li chemical shift reagent and [ N]-
isoquinoline (eq 3) as an inexpensive, relatively nonvolatile
pyridine surrogate.
6
1
0
15
8
profound aging effects spanning orders of magnitude. As to
11
the influence of LiCl, we observed nondescript lithium
enolate−LiCl mixed aggregates.
RESULTS
■
We confront the age-old problem of presenting data from a
variety of sources that, taken in total, provide the assignments
yet must be presented serially. We try to assist the reader by
prefacing the results with a detailed survey of the methods, as
well as the structural and stereochemical consequences of the
Myers enolates were generated at −78 °C with subsequent
aging for 10 min at 25 °C owing to slow aggregate
B
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Scheme 1. Synthesis of 15N-Labeled Enolate Precursorsa
Two-Dimensional NMR Spectroscopy. Critical spatial
relationships stem from a composite of NMR spectroscopies
13
(
COSY, TOCSY, HSQC, HMBC, and ROESY). Detailed
discussions of the cross-correlations without a computer
interface are poorly suited for print media. We only briefly
allude to important correlations herein. In a pedagogically
more tractable approach, a video tutorial in the Supporting
Information walks the viewer through some of the assignments,
10
as done in a previous paper. Pulsed field-gradient spin echo
NMR spectroscopy (PFGSE), or diffusion NMR spectroscopy,
was used semiquantitatively to determine relative aggregate
a
14
Reagents and conditions: (a) PhC(O)H, MgCl , TMSCl, NEt ,
sizes.
2
3
EtOAc, 24 h, rt; (b) TFA, MeOH, 10 min, rt; (c) TBDMSCl,
imidazole, DMF, 18 h, rt; (d) LiOH, H O , THF, 6 h, 0 °C to rt; (e)
Computations. Density functional theory (DFT) calcu-
lations were carried out at the B3LYP/6-31G(d) level with
energies from single-point calculations at the MP2 level of
2
2
1
5
(
(
COCl) , CH Cl , 2 h, rt; (f) NH Cl, NaOH, 30 min, 0 °C to rt;
2 2 2 4
g) [hydroxyl(tosyloxy)iodo]benzene, CH CN, 2 h, reflux; (h) acetic
15
3
theory. They largely showed plausibility of structural motifs,
formic anhydride, CH Cl , 1 h, −30 °C; (i) LiAlH , THF, overnight,
reflux; (j) propionyl chloride, NEt , THF, 10 min, 0 °C.
2
2
4
provided support to the correlation spectroscopies, and
allowed us to probe experimentally elusive three-dimensional
details. The energies proved unhelpful in distinguishing
structural and stereoisomers owing to resulting narrow
energetic ranges. The computations were crucial, however, in
predicting strong N−Li contacts that were eventually confirmed
spectroscopically and crystallographically. They also played a
central role in developing mechanistic and stereochemical
models.
Isomerism. Three general classes of isomerism alluded to
throughout the case studies required constant attention
because of their implications for symmetry and spectral
complexity. We also occasionally saw evidence of minor,
lower symmetry isomers. The three major forms of isomerism
are as follows.
3
8
equilibration. Although we focused on aggregates 4−6
prepared from propionate enolate 2, we examined the behavior
of 17 enolates that fall into several distinct categories: (1)
enolates 8 and 11 bearing small aliphatic enolate substituents
share common properties with enolate 2 that we comfortably
assigned by analogy to homoaggregate 4; (2) 7, 9, 10, 12, 19,
and 20, which manifest complex ensembles of otherwise sharp
resonances suggesting isomerism is at play yet form well-
defined heterochiral heteroaggregates sharing spectroscopic
properties with 5; (3) arylated enolates 13−18, which are
similar to one another but quite distinct from their aliphatic
counterparts, yet again appear to form distinct type-5
heteroaggregates; (4) enolate 21 is insoluble, and enolate 22
displays hopelessly broad resonances (possibly owing to
(
1) Helical isomerism is exemplified by mirror-image
fragments 23a and 23b, which become diastereomers when
stereogenic centers are included. Asymmetry within the
prismatic structure of 4 rendered concerns about helical
isomerism moot, but the possibility of such isomerism lingered
within our models for months.
1
instability mentioned by Myers).
MCV. We have developed general protocols for using MCV
in conjunction with NMR spectroscopy to characterize lithium
enolates. In its simplest form, MCV involves mixing binary
7
pairs of lithium enolate homoaggregates, An and B , of
n
unknown aggregation state, n, to generate an ensemble of
homo- and heteroaggregates (eq 4). In principle, the homo-
1
6
13
15
and heteroaggregates can be monitored using H, Li, C, N,
1
9
6
19
or F NMR spectroscopies. In practice, only Li and F NMR
spectroscopies played roles in this study. (Caveat: Large T ’s
1
6
6
for Li mandated up to 50 s pulse delays to attain accurate Li
integrations.) N NMR spectroscopy has been useful in MCV
when labeled substrates are available. Despite the requisite
1
5
12
15
resolution indicating that it would work well, [ N](R,R)-1 is
simply too precious. Plotting the relative concentrations of
different aggregates versus measured mole fraction of A (X )
(2) Isomerism resulting from N−Li bond scission and
reassociation to form different N−Li contacts (Scheme 2) is
represented by isomeric pairs 24/25 and 26/27. Chelates in
n
A
or B (X ) affords a Job plot (see Figure 7 for an example).
n
B
2
4 and 26 have phenyl moieties on the concave chelate face,
A + B ⇒ A + An−1B1 + An−2B2 + ... + Bn
(4)
n
n
n
whereas 25 and 27 have them on the convex face. Two-
dimensional spectroscopic probes of 4 and 5 show both types
(vide infra). Should only one of the multiple subunits reverse
chelate orientation, however, any existing symmetry would be
Choosing the right pairing partners to ensure sufficient
spectroscopic resolution of all homo- and heteroaggregates is
critical, largely empirical, and particularly challenging in this
case. The presumption is that the number and symmetries of
the heteroaggregates attest to the aggregation number of
homoaggregates A and B . For the first time in what is now
6
lost and the resonance counts would spike as each Li becomes
magnetically distinct.
(3) Positional isomerism such as that manifested in 24/26
or 25/27 pairs in Scheme 2 results from reversal of the enolate
and alkoxide roles. Such a transposition would break the high
symmetry.
Case 1: Homoaggregate of (R,R)-2. Structural studies of
the homoaggregate of propionate enolate (R,R)-2 are the focus
n
n
hundreds of applications, the homo- and heteroaggregates did
not share a common aggregation number. Therefore, we defer
discussing MCV-based studies until after presenting a more
conventional approach to assigning of the structure of
homoaggregate 4.
C
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Scheme 2. Isomerism Arising from Reversal of Chelate
Orientation or Enolate and Alkoxide Positioning
Early in the study, DFT computations of dianion subunits in
isolation or as part of larger aggregates evidenced strong N−Li
1
5
contacts, prompting us to insert an N label as shown in
1
5
6
15
Scheme 1. [ N](R,R)-2 showed Li− N coupling in the
downfield resonances at 2.32 and 2.35 ppm (J = 0.90 and
N−Li
1
.40 Hz, respectively), whereas the upfield resonances
remained as sharp singlets (Figure 1C). The corresponding
1
5
15
N NMR spectrum shows two 1:1:1 N triplets correlated by
single-frequency decoupling (Figure 1D).
Studies of solvation showed that only two of the four
lithiums (logically those lacking N−Li contacts) contain one
ligated THF each. For example, titrations of toluene solutions
of 2 with THF showed that only 0.5 equiv of THF per lithium
was required to convert broad mounds to the four character-
istic sharp resonances; additional THF caused minimal further
change. More surprisingly, free and bound THF were in slow
exchange on the NMR time scale at room temperature (Figure
2
A). Such slow ethereal solvent exchange on lithium is rarely
of this paper. Applications of MCV are deferred to subsequent
case studies.
6
Li NMR spectra of (R,R)-2 generated at −78 °C show
complex mixtures of resonances (Figure 1A). Full aggregate
1
Figure 2. Partial H NMR spectra of an aged solution of 0.10 M
(
(
R,R)-2 in 0.44 M THF and 9.1 M toluene-d at 20 °C. (A) Coupled;
8
B) single-frequency irradiated at 1.40 ppm.
17
observed and is without precedent at ambient temperature.
Single-frequency decoupling of the β protons on the bound
THF revealed a single AB quartet for the α protons (Figure
6
6
Figure 1. Li NMR spectra of a solution of 0.10 M [ Li](R,R)-2 in
neat (12.3 M) tetrahydrofuran (THF) recorded at −80 °C. (A)
Unaged; (B) aged at 25 °C for 10 min. Inset in spectrum B shows the
resolution at −40 °C. (C, D) NMR spectra of an aged solution of 0.10
2
B). Given that two magnetically inequivalent THF ligands
would show as many as four distinct AB quartets, we presumed
that a combination of free rotation about the Li−O bond and
near magnetic equivalence is at play. The decoupling was
mimicked using 3,3,4,4-tetradeuteriotetrahydrofuran (THF-
6
15
6
M [ Li, N](R,R)-2. (C) Li NMR spectrum recorded at −20 °C (to
improve resolution). (D) N NMR spectrum recorded at −80 °C.
1
5
18
d4), affording the same AB quartet.
6
equilibration required aging at 25 °C for 10 min, affording two
Pyridine functions as a Li NMR chemical shift reagent,
6
groups of Li resonances at chemical shift extremes in carefully
imparting large (>1 ppm) downfield shifts for pyridine-ligated
6
6
measured 1:1:1:1 proportions (Figure 1B). (The details of this
aging process are delineated below.) Varying the THF
concentration between 2.0 equiv per Li and 12.3 M (neat
THF) and the enolate concentration from 0.020 to 0.20 M
resulted in no change in relative integrations, indicating that
the resonances arose from either a single aggregate with four
magnetically inequivalent lithiums or two isomeric aggregates
in a precise 1:1 proportion. Failure to achieve coalescence at
Li nuclei and muted downfield shifts for more distal Li
10
resonances. Indeed, serial additions of pyridine to 2 showed
large (1.1−1.4 ppm) shifts of the formerly THF-bearing
6
lithiums and small shifts (∼0.4 ppm) of the Li resonances
coordinated by the carboxamide nitrogens. Readily available
1
5
11
and relatively inexpensive [ N]isoquinoline caused analo-
gous shifts and showed two of the four Li resonances as
6
doublets (JN−Li = 3.9 and 3.6 Hz) and the remaining two as
16
15
>
40 °C owing to slow inter- and intra-aggregate exchange, in
conjunction with requisite aging at ambient temperature,
attested to the remarkable robustness of the aggregate core.
sharp singlets (Figure 3). N NMR spectra showed broad
1
5
mounds rather than sharp resonances. Broad-band
N
6
decoupling caused the two Li doublets to collapse to singlets.
D
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octalithio derivatives with a symmetry element affording a
reduced resonance count (vide infra).
The full gamut of two-dimensional NMR spectroscopies led
to the assignment of all protons and carbons within the two
6
6
Figure 3. Li NMR spectra of aged solutions of 0.10 M [ Li](R,R)-2
1
5
at −95 °C: (A) 0.20 M THF; (B) 0.40 M [ N]isoquinoline and 0.20
M THF. The asterisk (*) flags THF−isoquinoline mixed-solvated 4.
Figure 4. Critical resonance correlations of the (R,R)-2-derived
homoaggregate.
The coupling constants are large compared with those of other
Li− N dative bonds.
The resonance count of the homoaggregate of 2 excludes a
single hexalithiated form by symmetry. The remaining options
shown in Chart 4 include (1) a 1:1 mixture of isomeric
6
15
17a
magnetically inequivalent subunits of (R,R)-2 (Figure 4). The
critical spatial correlations are as follows:
(
1) Multiple correlations between the two magnetically
distinct dilithio subunits excluded all models based on
pairs of isomers such as dilithio isomers 28 and 29, high-
symmetry tetralithio isomers 30 and 31, and helical
isomers 34 and 35.
Chart 4. Possible Di-, Tetra-, and Hexalithio Aggregates of
Enolate (R,R)-2
(
2) Strong intersubunit correlations resulting from Ph−Ph
contacts (a) and Me−H contacts (b) exclude tetralithio
isomers 30 or 31, as well as unsymmetrical tetralithio
isomers 32 and 33.
(
3) Apparent intra-subunit correlations suggest opposite
convexities, as drawn in Figure 4. The Me−Ph
correlations (c) and Me−H correlation (d) place the
phenyl moieties on the convex and concave faces,
respectively. We hasten to add, however, that deception
by inter-subunit interactions between two magnetically
equivalent subunits was a persistent concern. Moreover,
the isomer with the phenyl on the convex face, as in
subunit 1, is also calculated using simple (dilithio)
models to be >2.0 kcal/mol more stable.
(
4) Correlations a and b seem to exclude a number of
plausible aggregates by showing that both faces of both
subunits are proximate.
By eliminating all di-, tetra-, and hexalithio homoaggregates,
we were left with octalithio derivatives. Additional support
came from two independent measurements. A diffusion NMR
14
spectrum showed that the homoaggregate is larger than a
demonstrably hexalithio heteroaggregate (vide infra). We tried
using mass spectrometry (MS) on a DART MS, but the crude
effort suffered from considerable protonation problems and left
19
us leery of potential for user bias.
Considering all connectivities of octagonal prisms and
stacked cubes consistent with two inequivalent subunits and
four magnetically inequivalent lithium nuclei left eight prisms
and 18 stacked cubes as possible structures. Including the
restriction that subunits 1 and 2 have opposite convexities
(Figure 4), the number of possibilities reduces to six prisms
and 12 stacked cubes (Chart 5). The DFT-computed relative
energies showed plausibility but would not make the
assignment for us. The nastier problem was that none
accounted for the concurrent correlations without some
overtly optimistic interpretation.
dilithiated forms, such as isomers 28 and 29, displaying
different convexity, each with two magnetically inequivalent
lithium nuclei, (2) a 1:1 mixture of two high-symmetry
tetralithio isomers, such as 30 and 31, (3) a single low-
symmetry tetralithio form, such as 32 or 33, (4) either 30 or
3
1 paired with its helical isomer (not drawn but akin to 23a,b),
(
5) two high-symmetry hexalithio aggregates 34 and 35 (see
below) or analogous pairs of octalithio or higher polygonal
prismatic helical isomers, and (6) any one of a host of
E
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Chart 5. Renditions of DFT-Computed Structures Showing
a Representative Stacked Cube and Octagonal Prism of
Octalithio Homoaggregates of (R,R)-2
evidenced by intractable spectral complexity. This strategy
was doomed from the start given that two structurally distinct
Myers enolates can form seven distinct heteroaggregated
6
analogs of homoaggregate 4 manifesting 48 Li resonances.
Case 3: (S,S)-2−(R,R)-2 Heterochiral Heteroaggregates.
Mixing enantiomers of a single enolatesystematically
generating scalemic mixturesaffords type-ii heteroaggregates
with heterochiral subunits. A substantial advantage of this
strategy is that x/y and y/x heteroaggregates are mirror images,
which makes them appear spectroscopically as a single species,
thereby markedly reducing the resonance count and
minimizing resolution problems. By chance, heterochiral
enolates also optimize resolution and favor heteroaggregates
relative to homoaggregates nonstatistically. The fundamental
presumption of MCV for determining aggregation state fails,
however. Scalemic mixtures of octalithiated homoaggregates of
enolates afforded hexalithiated heteroaggregates without
exception (eq 5).
We needed an X-ray crystal structure. Early efforts failed, but
we eventually obtained a low-resolution crystal structure that
provided the needed insight (Figure 5). The structure of 4
For example, scalemic mixtures formed from (R,R)-2 and
S,S)-2 with requisite aging at 25 °C display six new Li
6
(
resonances in equal proportions (Figure 6A). The resonance
count precludes an octalithiated aggregate. Resonances with
midrange chemical shifts (1.0−2.0 ppm) proved to be
hallmarks of such heterochiral aggregates.
Monitoring the proportions of homo- and heteroaggregates
as a function of mole fraction X(R,R)‑2 afforded the Job plot in
Figure 5. Partial X-ray crystal structure of octalithiated enolate 4
showing the core with one subunit and the total structure missing four
THF ligands.
6
shows an S -symmetric core, which becomes a C -symmetric
4
2
octalithiated aggregate with the chiral appendages. The lithium
counts, N−Li contacts, and, most importantly, through-space
interactions match the resonance correlations without
6
15
exception. Differential Li− N coupling noted above is
reflected in markedly different N−Li bond lengths. Even
with a graphic interface, one has to look carefully to see two
pairs of subunits of opposite convexity. The pairs of
magnetically inequivalent THF ligands reside in environments
that appear so similar that the spectroscopic detection of a
single observable THF subunit is not surprising.
Case 2: (R,R)-2−(R,R)-8 Homochiral Heteroaggregates.
The use of MCV to characterize homoaggregated enolates is
based on the notion that mixtures of two homoaggregates will
produce a highly characteristic ensemble of heteroaggregates
(
eq 4). Taking a cue from previous studies of chiral β-amino
6
Figure 6. Li NMR spectra of aged solutions of enolate mixtures in
2
0
ester enolates, we examined three pairing strategies. The first
involved mixing combinations of enolates within a homochiral
series (mixtures of (R,R)-2 and (R,R)-8, for example) to
generate type-i heteroaggregates. Heteroaggregation was
6
neat THF at −80 °C: (A) 0.050 M [ Li](S,S)-2 and 0.050 M
Li](R,R)-2; and (B) 0.050 M [ Li, N](S,S)-2 and 0.050 M
[ Li, N](R,R)-2. The resonance labeled “alkoxides” corresponds to
monolithiated substrate.
6
6
6
15
[
15
F
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Figure 7. Although the data adequately fit to an all-hexalithio
subunit 3 is isolated from subunits 1 and 2 and displays no
intersubunit correlation.
(
trimer) model, the fit in Figure 7 corresponds to that derived
Figure 9. Critical resonance correlations of subunits in the
hexalithiated heterochiral aggregate formed from (R,R)-2 and (S,S)-2.
Figure 7. Job plot showing the relative integrations of octalithio
homoaggregates (R /S ) and hexalithio heteroaggregates (RS /R S)
Labeling studies showed that the hexalithio heteroaggregates
4
4
2
2
represented an aggregate that was altogether different from
21
6
versus intended mole fractions of [ Li](R,R)-2 (X ) for 0.10 M
R
15
6
that of octalithio homoaggregate 4. In mixtures of [ N](R,R)-
mixtures of enantiomeric lithium enolates [ Li](R,R)-2(R) and
1
5
6
6
2 and [ N](S,S)-2, the resonance at 1.95 ppm appeared as a
doublet (JN−Li = 1.25 Hz), whereas the resonance at 1.83 ppm
appeared as a doublet of doublets (JN−Li = 1.30 and 2.17 Hz).
This result indicates that two nitrogens are bound to a common
lithium (Figure 6B). The remaining four upfield resonances are
[
Li](S,S)-2(S) in neat THF at −80 °C monitored with Li NMR
spectroscopy. The curves result from a parametric fit to a tetramer−
trimer model.
20
1
5
15
for octalithio homoaggregates (tetramers) and hexalithio
singlets. The N NMR spectra showed three N triplets with
20
heteroaggregates (trimers). (Recall that only two spectro-
scopically discrete species exist.) The requisite fitting protocols
are in the Supporting Information. The maximum at 0.50
derives from the superposition of enantiomeric 2:1 and 1:2
heteroaggregates. One could easily imagine confusing the
maximum as evidence of a tetralithio heteroaggregate (dimer)
if not for the resonance count and poor fit.
correlations confirmed by single-frequency decoupling. Mix-
15
tures of (S,S)-2 and [ N](R,R)-2 in which only one substrate
15
is N labeled caused the lithium central to the N−Li−N
fragment to appear as a doublet at all proportions of the two
enolates. Thus, the subunits forming the N−Li−N contact,
subunits 1 and 2 in Figure 9, are necessarily heterochiral as
drawn. From connectivities alone, we could draw six isomeric
cores with a central N−Li−N contact. Including additional
restrictions imposed by the heterochiral core and established
convexities, we were left with two pseudo-octahedral partial
structures, 36 and 37, displaying cores that would be delta
The relative and absolute aggregation state of heteroag-
gregate 5 was supported by diffusion NMR spectroscopy
showing that the hexalithio appeared to be smaller than the
14
octalithio (Figure 8). In fact, showing the reverse (the
octalithio is larger than the more easily characterized
hexalithio) was more important.
22
isomers. There are eight possible isomers obtained by the
placement of either (R,R)-2 or (S,S)-2 as the third subunit
(with positional isomerism considered). The gross structure of
The gamut of two-dimensional NMR spectroscopies
provided the key resonance correlations for the three discrete
subunits of 5 shown in Figure 9. The convexities as drawn
derive from the correlations labeled a, d, and e. Notably,
1
13
hexalithiated aggregate 5 relied on H and C correlation
spectroscopy (Supporting Information). From the eight
possible isomers, DFT computations suggested that the isomer
shown as aggregate 5 with the 36 core is the most stable by >4
kcal/mol (Figure 10).
Case 4: (R,R)-8−(S,S)-11 Heterochiral Heteroaggregates.
Pairing enolates of opposite absolute configuration and
containing different enolate substituents affords type-iii
heteroaggregates displaying many of the properties of the
heterochirality observed in case 3 but with magnetically
distinct R′S and R′ S heteroaggregates (eq 6). Heterochiral
2
2
binary combinations of 2, 8, and 11 were all tractable.
Emblematically, mixtures of (S,S)-8 and (R,R)-11 displayed
fully desymmetrized 2:1 and 1:2 heteroaggregates each with
affiliated six equal-intensity resonances (Figure 11). Unlabeled
debris in the spectra of both homo- and heteroaggregates is
reproducible, implicating minor stereoisomers. Although
detailed correlating spectroscopic analyses would offer margin-
al gain at great effort, monitoring the aggregates versus mole
fraction of (R,R)-11, X(R,R)‑11, affords the Job plot shown in
Figure 12. The use of measured rather than intended mole
Figure 8. Plot of diffusion coefficient (D) from diffusion NMR
spectroscopy versus molecular weight of an aged solution of 0.040 M
(
S,S)-2 and 0.060 M (R,R)-2 in neat THF at −60 °C; y = a + bx, a =
4.622, b = 0.443. This experiment assumes four coordinated THF
ligands per homotetramer and four per heterotrimer.
−
21
fraction is especially suited for such mixtures.
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Figure 12. Job plot showing the relative integrations of octalithio
homoaggregates and hexalithio heteroaggregates versus measured
6
mole fractions of [ Li](R,R)-11 (X ) for 0.10 M mixtures of lithium
R′
6
6
enolates [ Li](S,S)-8(S) and [ Li](R,R)-11(R′) in neat THF at −80
6
°
C monitored with Li NMR spectroscopy (Figure 11). The curves
20
result from a parametric fit to a tetramer−trimer model.
Figure 10. DFT-computed structure of the most stable hexalithiated
enolate aggregate, 5, showing the Li O core (left) and distorted
6
6
octahedral core described by 36 (right).
6
6
Figure 13. Li NMR spectra of 0.10 M solutions of [ Li](S,S)-16 (S)
6
and [ Li](R,R)-14 (R′) in neat THF at −80 °C at the ratios indicated
on the spectra.
6
6
Figure 11. Li NMR spectra of 0.10 M solutions of [ Li](S,S)-8(S)
6
and [ Li](R,R)-11(R′) in neat THF at −80 °C. The measured mole
6
fractions of [ Li](R,R)-11 (X ) are 0.00, 0.40, 0.57, and 1.00 for A−
homoaggregate is smaller than the hexalithio heteroaggregate
R′
D, respectively.
(
vide infra). Attempts to obtain X-ray quality crystals of the
homoaggregates were unsuccessful.
Heterochiral mixtures of arylated enolates (S,S)-14 and
(
R,R)-16 showed clear evidence of hexalithiated heteroag-
6
gregates, but spectral overlap precluded a Job plot using Li
NMR spectroscopy. The single fluorine nucleus per subunit (as
6
19
opposed to two Li nuclei) enables F NMR spectroscopy
1
9
while cutting the resonance counts in half. The F NMR
spectrum shows a single resonance (Figure 14) despite
normally high resolution of F NMR spectroscopy. Mixtures
1
9
1
9
Case 5: (R,R)-14−(S,S)-16 Heterochiral Heteroaggregates.
Myers enolates with sterically demanding yet anion-stabilizing
aryl substituents show behaviors that are distinctly different
from those of their aliphatic counterparts (see Figure 1A).
Each displays a major upfield resonance accompanied by a
minor resonance in ratios that vary from enolate to enolate
showed that the 1:2 and 2:1 F pairs are consistent with a
hexalithiated species. Minor isomers of the 2:1 and 1:2
heteroaggregates also were observable. Monitoring the homo-
and heteroaggregates versus X(R,R)‑14 and arbitrarily assigning
the homoaggregates as hexalithio, tetralithio, or even dilithio
afforded reasonable Job plots. The plot in Figure 15 arbitrarily
assumes a tetralithiated homoaggregate.
(
Figure 13). The intensities are invariant to changes in enolate
23
concentration, suggesting that they are isomers. The absence
of downfield resonances shows that the aryls cause deep-seated
structural changes. High steric demands and anion stabilization
of the phenyl moiety would be expected to promote lower
Case 6: (R,R)-2−LDA Mixed Aggregate. As a standard
control experiment, lithium enolates were generated from
6
15
9
[ Li, N]LDA to identify any resonances attributable to
LDA−enolate mixed aggregates. Although resulting LDA-
derived mixed aggregate 6 bore little relationship to
2
4
aggregates. Diffusion NMR spectroscopy confirmed that the
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6
6
Figure 14. 19F NMR spectra of 0.10 M solutions of [ Li](S,S)-16 (S)
6
Figure 16. Li NMR spectra of 0.10 M solutions of [ Li](R,R)-2 and
6
6
0
.20 M LDA in neat THF at −80 °C using (A) [ Li]LDA, (B)
and [ Li](R,R)-14 (R′) in neat THF at −80 °C. The measured mole
6
15 6 15 15
6
[
Li, N]LDA, and (C) [ Li, N]LDA and [ N](R,R)-2.
fractions of [ Li](R,R)-14 (X ) are 0.00, 0.34, 0.67, and 1.00 for A−
R′
D, respectively.
revealed favorable N−Li contacts, and supported tetrasolva-
tion, as displayed in Figure 17.
Lithium Chloride: Influence on Structure. Addition of LiCl
to a pre-aged solution of aggregate 4 had no measurable effect
(
Figure 18A): aggregate 4 was observed along with free LiCl at
the anticipated relative proportions. Warming the probe in 20
C increments caused no broadening of the resonances of 4 or
°
appearance of new resonances. Careful integration of the
resonances, however, showed that the broad mound
corresponding to LiCl increased at the expense of 4 (Figure
1
8B−F). The mound appeared to include free LiCl in rapid
exchange with a LiCl−enolate adduct(s) denoted non-
descriptly as 2 . Assuming conservation of mass, the
LiCl
proportions of homoaggregate 4 and 2LiCl could be teased
out. Plotting the percent of enolate 2 that existed as
homoaggregate 4 versus temperature (Figure 19) showed
limited adduct formation at low temperatures and a marked
change (a discontinuity) at ∼0 °C. Reversing the protocol
Figure 15. Job plot showing the relative integrations of tetralithio
homo- and hexalithio heteroaggregates versus measured mole
6
fractions of [ Li](R,R)-14 (X ) for 0.10 M mixtures of lithium
R′
6
6
enolates [ Li](S,S)-16(S) and [ Li](R,R)-14(R′) in neat THF at −80
1
9
°
C monitored with F NMR spectroscopy (see Figure 14). The
cooling the probe in 20 °C incrementsdid not reverse the
20
25
curves result from a parametric fit to a dimer−trimer model.
changes; 2 remained dominant. The spectrum rerecorded
LiCl
at −80 °C may include additional debris that corresponds to
species in slow exchange at −80 °C, but it appears
26
homoaggregate 4, it foreshadowed the unusual N−Li−N
connectivity in heteroaggregate 5.
insignificant. Adduct formation was confirmed by LiCl-
1
13
dependent chemical shifts observed in the H and C NMR
27
Mixtures of enolate (R,R)-2 with varying amounts of excess
Li, N]LDA included LDA homodimer, homoaggregate 4,
spectra. The time-averaged resonances may be concealing
multiple LiCl adducts of varying LiCl stoichiometries as
discussed below. Although adduct 2LiCl cannot be charac-
terized, it is decidedly important (vide infra).
[6
15
26
and mixed dimer 6. The key characteristics of 6 were as
6
follows: (1) four Li resonances appeared in a 1:2:2:1 ratio
(
Figure 16A), indicating a hexalithiated species with a
Lithium Chloride: Influence on Subunit Exchange. In a
fairly crude experiment, kinetically formed (pre-aged)
ensembles of 2 (see Figure 1A) were warmed in 20 °C
increments with cooling to −80 °C at each temperature level
6
symmetry element; (2) the two major Li resonances appeared
as doublets (J = 5.45 and 5.45 Hz) owing to splitting by a
single LDA-derived 15N nucleus (Figure 16B); (3) the mixed
aggregate prepared from [ N](R,R)-2 and [ Li]LDA caused
one of the minor resonances not connected to the LDA
fragment to appear as a triplet (J = 2.4 Hz; Figure 16C), which
15
6
6
to record the Li spectra. The spectra indicate that aging to
form 4 becomes consequential at >0 °C. Repeating the
experiment with added LiCl showed little or no effect on the rate
of aging.
15
1
correlated with one N triplet (1:1:1). The gamut of H and
1
3
C NMR spectroscopies showed a single subunit with the
In a cleaner experiment, samples of (S,S)-2 and (R,R)-2
were separately and fully aged before mixing to form a racemic
mixture of aggregate 4. Warming in 20 °C increments revealed
hexalithiated heteroaggregate 5, evidencing that interaggregate
subunit exchange on laboratory time scales emerges only at 40
°C. (Subunit exchange in the octalithiated homoaggregate is
slower than exchange in unaged ensembles.) The same
experiment with added LiCl showed that rate of conversion
phenyl moiety in the convex face, as drawn for 6. The
stoichiometry, symmetry, and coupling demanded a hexalithio
mixed aggregate with a C symmetry axis. The symmetry
2
demanded that the dianions reside on opposite faces of 6.
Although pyridine caused marked chemical shifts, attempts to
15
probe solvation using [ N]-isoquinoline failed owing to
decomposition. DFT computations showed that 6 is viable,
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Figure 17. Structure of enolate−LDA mixed aggregate 6. The four solvents supported by DFT computations have been omitted in the computed
rendition for clarity.
alkoxide.) The apparent percent conversions were confirmed
1
with workup and H NMR spectroscopic analysis of the crude
products. Fully aged homoaggregate 4 was marginally reactive
toward allyl bromide at 0 °C for 1.0 h (Figure 20). Myers also
Figure 18. 6Li NMR spectra of a pre-aged 0.10 M solution of
6
[
Li](R,R)-2 with subsequent addition of 0.20 M LiCl in neat THF-d8
recorded at incrementally rising temperatures.
Figure 20. Rates and percent conversions of alkylation of lithium
enolate (R,R)-2 (0.040 M) in neat THF at −60 °C by allyl bromide
(0.092 M) with various amounts of LiCl.
noted such low conversions (10−13%). Varying the THF
molarity offered no improvement. Elevated temperatures
promoted O-alkylation byproducts. Reasoning that unaged
samples contain structures that are less stable and, thus, more
reactive, we found that addition of allyl bromide 1.0 min after
enolization at −20 °C improved the conversion to 40%.
Completely unaged samples kinetically formed at −78 °C (see
Figure 1A) alkylated at −78 °C to 67% conversion before stalling.
Surmising that the ensemble of unstable aggregates generated
at −78 °C might depend on the source, we showed that
metalation with lithium 2,2,6,6-tetramethylpiperidide increased
the conversion to 78%, which proved to be the upper limit.
Attempts to push the conversion of unaged samples through
gentle warming failed, presumably because of competing aging
to less reactive forms.
Figure 19. Plot of percent enolate 4 in solutions of a pre-aged 0.10 M
solution of [ Li](R,R)-2 with subsequent addition of 0.20 M LiCl in
6
neat THF-d versus temperature (Figure 18). Incremental temper-
8
ature increases (black) were followed by incremental temperature
decreases (blue).
of the two antipodes of 4 to give 5 occurs at >0 °C. Thus, LiCl
influences the aging rate on laboratory time scales but only
marginally and, as we discuss below, much more slowly than the
alkylation.
Aging Effects on Enolate Reactivity. We now present
some curious observations on how aggregate aging and the
stabilities of the aggregates influence their reactivities.
Alkylations using allyl bromide (eq 7) were monitored using
in situ IR spectroscopy following the formation of the product
Influence of LiCl on Reactivity. It is not surprising that
homoaggregate 4 is inert; it looks inert. Addition of ≥5.0 equiv
of LiCl as part of Myers’s optimized protocol is imperative. A
more granular view obtained by adding various concentrations
of LiCl to the allylation in eq 7 reveals a burst of reactivity
−1
−1
alkoxide at 1610 cm . (The enolate absorbance at 1640 cm
was poorly resolved from an absorbance of the product
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followed by stalling to the rate that approximates the LiCl-free
rate (Figure 20). Both the initial rates and the percent
conversions were promoted by elevated LiCl concentrations.
We attribute the acceleration to the nondescript adduct(s)
denoted as 2LiCl and the stalling to an equally nondescript
autoinhibition resulting from a lithium alkoxideLiCl mixed
28
aggregate that occludes the LiCl. Monitoring the alkylation
6
with Li NMR spectroscopy revealed only homoaggregate 4.
6
The Li resonances of the product alkoxide were absorbed into
the broad LiCl-derived mound in rapid time-averaged
exchange.
Monitoring the initial alkylation rates proved instructive.
The initial rates indicate a clean first-order dependence on allyl
bromide (Figure 21) attesting to the general quality of the data
Figure 23. Plot of initial rate constants (kobsd) versus the
concentration of (R,R)-2 for allylation in eq 7 with 0.080 M LiCl
and 0.18 M allyl bromide in neat THF at −60 °C. The asterisk (*)
denotes a point at 0.010 M enolate; the absorbance at 0.010 M
enolate is too low to be considered fully reliable. The curve depicts an
unweighted least-squares fit to the function f(x) = ax /(bx + 1) such
that a = 0.014 ± 0.0043, b = 48 ± 18, and m = 1 (set value).
m
m
clearly supported the curvatures in Figures 22 and 23 as
saturation kinetics.
The red curve in Figure 22 represents first-order saturation
behavior required if the equilibrium in eq 8 affords 2LiCl as a
monomer-based tetralithiated mixed aggregate, (enolate)-
(
LiCl) (eq 8, 1/n = 1 and 1/m = 1/4). The blue curve
2
shows a fit with n as an adjustable parameter and fits to a
second-order LiCl saturation (1/n = 2 and 1/m = 1) consistent
with 2LiCl as a tetramer-based mixed aggregate, (enola-
Figure 21. Plot of initial rate constants (kobsd) versus allyl bromide
concentration for alkylation of 0.040 M (R,R)-2 and 0.040 M LiCl in
neat THF at −60 °C. The curve depicts an unweighted least-squares
te) (LiCl) . We hasten to add that the quality of the fits
4
4
n
−2
fit to the function f(x) = ax such that a = (1.2 ± 0.26) × 10 and n
distinguishes the various possible structures for 2LiCl in
principle but, in our opinion, not in practice. The enolate
dependence in Figure 23 is fit to a first-order saturation
behavior (eq 8, 1/m = 1), but a fit to a fractional-order
saturation behavior (1/m = 1/4) is, practically speaking,
indistinguishable. Plotting the initial rates versus THF
concentration in hexane (Figure 24) reveals an upward
curvature suggesting intermediate first or second order.
=
1.1 ± 0.19.
2
9
and a rate-limiting alkylation. Curvatures in the LiCl
dependence (Figure 22) and enolate dependence (Figure
2
3) could be construed as fractional-order dependencies
emblematic of dimer−monomer and tetramer−monomer
dissociations. Detection and quantitation of 2 , however,
2
8
LiCl
The saturation behaviors are consistent with the generic rate
law in eq 9. Two critical pieces of information remained
outstanding: (1) the structure of 2LiCl as described in eq 8 is
Figure 22. Plot of initial rate constants (kobsd) versus LiCl equivalence
(per enolate) for alkylation of 0.040 M (R,R)-2 and 0.092 M allyl
bromide in neat THF at −60 °C. The red curve depicts an
n
n
unweighted least-squares fit to the function f(x) = ax /(bx + 1) such
Figure 24. Plot of initial rate constants (kobsd) versus THF
concentration for alkylation of 0.040 M (R,R)-2 with 0.040 M LiCl
by 0.092 M allyl bromide in hexanes cosolvent at −60 °C. The curve
−
4
that a = (1.6 ± 0.34) × 10 , b = 0.57 ± 0.25, and n = 1 (set value).
The blue curve depicts an unweighted least-squares fit with n as an
−
4
n
adjustable parameter such that a = (2.3 ± 0.86) × 10 , b = 1.2 ±
.52, and n = 2.1 ± 0.77.
depicts an unweighted least-squares fit to the function f(x) = ax such
−
4
0
that a = (0.042 ± 0.020) × 10 and n = 1.5 ± 0.21.
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unknown, leaving the values of m and n in eq 9 undefined, and
to a definitive structural assignment. Attempts to use MS to
1
9
(
2) the reaction order in 2LiCl could not be measured owing to
determine aggregation presented potentially resolvable
technical challenges that rendered the data from our first
effort at risk of user-dependent interpretation. DFT compu-
tations often help resolve structural issues, but there were
simply too many possible isomers in a narrow energetic range.
After several years of study, a low-quality crystal structure
provided the answer key: the solution structural studies came
together into a fully coherent structural model. While we had
obsessed over octagonal prisms and stacked cubes, the
octalithiated aggregate proved to be 4, the core of which was
solubility constraints; knowing this would provide an
important clue about the structure of 2LiCl. We consider
three mechanisms in the Discussion.
1
/m(enolate) + 1/n(LiCl) F (enolate)4/m(LiCl)2/n
4
2
4
2LiCl
(8)
1
/n
1/m
d[product]/dt = k[RBr][LiCl] [enolate]
1
/n
/
(1 + k′[LiCl] [enolate]1/m)
(9)
6
known.
MCV consumed considerable attention. By intent, mixtures
of structurally similar homoaggregates afford ensembles of
heteroaggregates with numbers and symmetries that attest to
the structures of the homoaggregates. However, mixtures of
octalithiated homoaggregates, dozens of combinations in total,
afforded hexalithiated heteroaggregates. To the best of our
knowledge, this failure of MCV is a first for us. A detailed study
of two antipodes of enolate 2 revealed the heterochiral
heteroaggregate of type 5. Aside from the different aggregation
numbers of 4 and 5, the hexalithiated heteroaggregates include
strikingly different structural details.
DISCUSSION
■
Myers’s central insight, which made pseudoephedrine-derived
enolates popular reagents for asymmetric alkylations, was that
excess LiCl is critical to obtaining high yields. From a
structural and mechanistic perspective, the dianionic enolates
present a host of challenges outlined in the introduction that
are unlike any we have confronted to date.
Structural Studies: Protocols. The aggregate structures
are summarized in Scheme 3, but they tell only a small part of
Scheme 3. Structural Summary
Structures. Let us take a granular peek at structural details
30
of the homo- and heteroaggregates and mixed aggregates
summarized in Scheme 3.
Aging Effects. Implicitly embedded in Myers’s alkylation
protocols are aging effectsrequisite warming cyclesthat
prove to have a firm structural basis and became a major focus
of our studies. Enolization at −78 °C affords a complex
mixture that converges to form octalithiated aggregate 4 only
on warming to ambient temperatures. The same aging effects
are observed during formation of heteroaggregates of type 5.
Although aging to form 4 could be construed as the structural
change that Myers addressed by warming the samples, this
conclusion is incorrect. The aging was needed to generate LiCl
adducts (below).
N−Li contacts. The N−Li contacts of carboxamide-derived
enolates appear to have gone undocumented until now. We
discovered them computationally and then took them seriously
1
5
enough to confirm them using N-labeled substrate.
Contemporaneously, Williard and co-workers crystallographi-
cally detected a number of such N−Li contacts in structurally
31
simple carboxamide enolates. How general they are in
1
5
solution remains unknown; a simple N-labeled propionamide
32
enolate affords no N−Li coupling. From the outset, the
importance of the N−Li contacts and the resulting convexity in
the Myers enolates seemed certain to underlie the stereo-
control.
Slow THF exchange. It is rare that lithium-bound THF at
ambient temperatures is surprising. It is rare that THF can be
observed in the slow exchange limit even at low temper-
17
atures. We suspect that the slow exchange on aggregate 4
the story. The number of analytical methods and tactics is
unusual. These include a bevy of two-dimensional correlation
derives, at least in part, from suppression of the associative
17a
pathway. Although slow alkylations of 4 probably render
rates of THF exchange irrelevant, highly reactive electrophiles
could suffer consequentially (stereochemically) from restricted
access to coordination sites.
Stereochemically sensitive aggregation. The formation of
octalithiated homochiral aggregates of type 4 and hexalithiated
heterochiral heteroaggregates of type 5 are, in one sense, an
idiosyncratic artifact of using MCV to study aggregation. (We
are likely the only group to intentionally study racemates of
6
15
spectroscopies, Li− N double-labeling studies, diffusion
NMR spectroscopy, mass spectrometry, IR spectroscopy,
MCV, X-ray crystallography, and DFT computations. This
breadth of effort was demanded by the elusiveness of the
answers rather than by some predilection toward thorough-
ness.
Standard H and 13C NMR two-dimensional correlation
1
spectroscopies provided critical information but did not lead us
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2
0
chiral lithium enolates used in asymmetric synthesis.)
Mixed Aggregation. Lithium chloride forms a nondescript
mixed aggregate denoted simply as 2LiCl (eq 8). Formation of
2LiCl is slow at −80 °C and occurs in earnest only near ambient
temperatures on laboratory time scales (eq 13). It is the slow
formation of 2LiCl that Myers seems to have overcome by
warming the enolate−LiCl mixtures before alkylating the
enolates. An odd temperature dependence (Figure 19) shows
that the formation of 2LiCl is slow and irreversible. It also
suggests, however, that other partial adducts at intermediate
Nonetheless, the hexalithiated heteroaggregates display a
fundamentally different doubly chelated N−Li−N core (see
6 and 37). This structural feature is shared by LDA mixed
3
aggregate 6 (Figure 17). The hexalithiated aggregates are also
formed nonstatistically. The good news is that DFT studies
suggest that the homochiral hexalithio derivatives prefer
heterochirality (eq 10) and the octalithiated forms prefer
homochirality (eq 11). The dubious result is that, when
combined, DFT computations completely fail to predict
hexalithiated aggregates of type 5 to be competitive with
homoaggregate 4 (eq 12).
temperatures may exhibit limited reactivity. Once 2
the time averaging of free and bound LiCl in the Li NMR
forms,
LiCl
6
spectra (eq 14) made it difficult to detect (we almost missed
35
it) and difficult to characterize to date. The potentially
−
6.9 kcal/mol
R + S Hooooooooooo oo I R S + RS
(10)
(11)
(12)
critical observation is that exchange of free and bound LiCl, as
3
3
2
2
6
well as intra-aggregate exchanges of the Li nuclei within 2LiCl,
+
8.6 kcal/mol
R + S Hooooooooooo oo I R S + RS
are exceedingly facile on NMR time scales at −80 °C.
4
4
3
3
>
20 kcal/mol
R + 3S HooooooooooooI 4R S + 4RS
3
4
4
2
2
Aging Effects on Reactivity. If one supposes that all
aggregated forms converge on a fleeting dilithiated (mono-
meric) intermediate, then aggregate stability and reactivity
should correlate inversely (Scheme 4). Fully aged 4 reacts
Autoinhibition. Alkylation of enolate 2 with allyl bromide
stalls at percent conversions that qualitatively correlate with
the added LiCl. In theory, this result could stem from
incomplete formation of 2LiCl, but we cannot push the percent
conversions effectively even under conditions in which LiCl
could be recycled. We surmise that the product of the reaction,
an alkoxide (R′OLi), occludes LiCl in a mixed aggregate (eq
Scheme 4. Reactivity of Myers Enolate 2 without Added
LiCl as Measured by Percent Conversion after 1 h
15). Once again, strikingly fast LiCl exchange did not refute
the existence of such an adduct but did preclude structural
studies.
cat. LiCl
nLiCl
4
+ RBr ⎯⎯⎯⎯⎯⎯ ⎯→ (R′OLi) HooooI (R′OLi)(LiCl)
n
(product)
(15)
It is instructive to ponder the structure of 2LiCl (Chart 6).
The deep-seated structural changes in LiCl adducts 38 and 39
Chart 6. Possible Structures of Enolate−LiCl Adduct 2LiCl
slowly at 0 °C and stalls at <10% conversion, whereas unaged
aggregatesthe complex ensemble of species formed kineti-
cally at −78 °Care orders of magnitude more reactive,
eventually stalling at 67−78% conversion. Presumably, the
kinetically formed ensemble contains aggregates of varying
reactivities. One cannot help but worry that the depiction of 5
may be susceptible to correction in its detail.
The Role of LiCl: Enolate Structure and Reactivity.
1
Adding excess LiCl is imperative, as noted by Myers, and it
serves the dual function of accelerating the alkylation and
allowing the reaction to proceed to full conversion (Figure 20).
We considered several possible roles for LiCl.
Catalyzed Deaggregation. One could imagine that LiCl
catalyzes tetramer−monomer exchange, shifting the rate-
limiting step from deaggregation to alkylation of the
are appealing in light of remarkably low rates of LiCl
incorporation, although 39 contains one or two LiCl fragments
depending on whether the counterion is a simple or a cationic
28,34
33
dissociated monomer.
LiCl-catalyzed LDA deaggregation2
8
36
was studied and documented in excruciating detail.
triple ion. Chloride-derived “ate” complexes analogous to 39
Presuming that a catalyzed deaggregation would affiliate with
a catalyzed exchange of subunits, we probed the influence of
LiCl on rates of subunit exchange from a number of angles.
Minor accelerations of subunit exchanges occurring on
laboratory time scales near ambient temperatures were
observed, but they could not explain LiCl-mediated alkylations
at −60 °C.
and 40, in which one could think of chloride as a
hexamethylphosphoramide surrogate, have been observed
37
and are computationally viable (Supporting Information).
Retention of the intact octalithio framework, as depicted in 40,
cannot be rigorously excluded (it is a computational
minimum), but the spectroscopic properties of 2LiCl argue
against the intact Li O core.
8
8
M
DOI: 10.1021/jacs.9b00328
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Scheme 5. Mechanism of Alkylation of Cubic Mixed Aggregates
Rate Studies and Mechanism. Detailed rate studies
reveal curvatures consistent with saturation kinetics reflecting
the lithium enolate- and LiCl-dependent formation of 2LiCl
The third and simplest of the three mechanisms is based on
direct alkylation via dilithiated monomer-based transition
structure 43 stripped free of any LiCl influence. Although
the model could readily account for the THF dependence, it
also predicts a net inverse LiCl dependence of some form
owing to requisite dissociation of LiCl from 2LiCl. We can
easily imagine such details evading our detection by being
embedded in the saturation kinetics required to form 2LiCl
(Figure 22). This monomer-based transition structure 43 is
computationally preferred relative to the three other choices
(Supporting Information) and is consistent with experiment.
On first inspection, the notion that forming a LiCl adduct to
simply dissociate it before alkylation seems to defy the
Principle of Detailed Balance, which suggests that in such an
ensemble the LiCl should impart a positive influence on rates
(
(
Figures 22 and 23). The accompanying THF dependence
Figure 24) is compatible with almost any model with some
imagination. We have considered a number of mechanisms for
the alkylation that hinge on the structure of 2LiCl with a focus
on mixed aggregates 38 or 39. We present a working
hypothesis based on 38 as described by eq 16 and delineated
in Scheme 5.
Computational studies suggest a preference for 38a relative
to 38b, displaying the opposite convexity in the resting state
that superficially follows through to the most stable transition
structures 41a and 41b. The mechanism also includes no
provisions for an additional THF suggested by the rate studies,
but that does not trouble us too much. The more systemic flaw
is that the preference for transition structure 41b predicts the
wrong (minor) isomer compared with that observed exper-
imentally.
38
only if it is included in the rate-limiting transition state. Yet
the Principle of Detailed Balance applies only to ensembles of
species in equilibrium. The Myers enolate and its LiCl adduct
(eq 17) are not at equilibrium; the reluctant formation of 2LiCl
requires ambient temperatures, affording 2LiCl, which seems to
be in rapid exchange with monomer but slow exchange with
homoaggregate 4. The role of LiCl is to overcome the
otherwise insurmountable barrier to dissociating octalithiated
prismatic tetramer 4. An analogous example of aggregate
ensembles in which not all species are at equilibrium was
recently observed for Evans enolates in which facile dimer−
monomer equilibration occurs concurrently with slow
‡
(
enolate)(LiCl) + RBr → [(enolate)(LiCl) (RBr)]
(16)
2
2
An alternative mechanism that could account for THF-
dependent rates (maybe too much so depending on the resting
state of 2LiCl) is based on LiCl ate complexes such as 39. Such
3
7
+
ate complexes have been observed as have simple Li(THF)
n
36
and more complex triple-ion-based counterions. The model
reveals a strong (2.5 kcal/mol) preference for transition
structure 42 relative to the second most stable of three other
isomeric transition structures (Supporting Information). This
model is consistent with the experimental results.
8d
formation of the more stable and unreactive tetramer.
LiCl/0 °C
−78 °C
(
ROLi) ⎯⎯⎯⎯⎯⎯⎯⎯ ⎯→ (ROLi)(LiCl) HooooooI
slow
fast
LiC
4
n
4
2
[
ROLi] + (LiCl) (THF)
(17)
2
4
Inspection of the transition structures (12 in total) with the
aid of a graphical interface reveals no self-evident insight into
the stereochemical preferences. There is no visibly discernible
preference for a specific convexity of the chelated dianion or
for an approach of the allyl bromide to the enolate that can be
generalized. Notably, however, one can see a lengthening of
the N−Li bond at the transition structure as the loss of the
enolate character at the transition states attenuates the Lewis
basicity of the nitrogen ligand. IRC calculations indicate that
N
DOI: 10.1021/jacs.9b00328
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
the alkylation causes complete scission of the N−Li bond
during the alkylation.
precursors were prepared by acylating the pseudoephedrine as
described in Supporting Information.
NMR Spectroscopy. Individual stock solutions of substrates and
LDA were prepared at room temperature. 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 LDA (2.1 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 indefinitely in
a freezer −86 °C. Each sample routinely contained 0.10 M total
Omitting Lithium Chloride? A potential impediment to
using Myers enolates on pilot-plant or plant scales stems from
the relatively high dilutions (0.10 M) imposed by the limited
solubility (and cost) of the ≥5-fold LiCl excess. Evidence that
precluding enolate aging markedly enhanced reactivities and
percent conversions in halide-free solutions offered reason for
optimism, but we could not push past 78% conversion.
Investigators at Merck were able to exclude LiCl in the
alkylation of a highly stabilized enolate bearing an aryl group
1
6
13
15
enolate with a 0.010 M excess of LDA. Standard H, Li, C, N, and
1
9
3e
F NMR spectra were recorded on a 500 MHz spectrometer at
akin to enolates 13−18 using THF/TMEDA, but we showed
those are structurally quite different than the more standard
Myers enolates. It would be tempting to add ligands to
selectively extract LiCl from the putative product mixed
4
99.92, 73.57, 125.72, 50.67, and 470.33 MHz, respectively.
6
Quantitated Li integrations required the relaxation delay set to
seven times the decay half-life. Integration of NMR signals were
carried out using a line-fitting method. The Li and C resonances
are referenced to 0.30 M [ Li]LiCl/MeOH at −90 °C (0.0 ppm) and
the CH O resonance of THF at −80 °C (67.57 ppm). Two-
6
13
+
−
aggregate by forming Li (ligand)//Cl (eq 18), but according
to the Principle of Detailed Balance, such a side equilibrium
would decrease the concentration of 2LiCl as well. Nonetheless,
we tried a few chelating ligands to no avail. We have, however,
been making progress using a radically different strategy, but
that story will have to wait.
6
2
dimensional NMR spectroscopies (COSY, TOCSY, HSQC, HMBC,
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
ligand
−1
+
−
of 4 cm . A representative reaction was carried out as follows: The IR
(
R′OLi)(LiCl) Hooo oo I [R′OLi] + Li (ligand)// Cl
n
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 2 in THF or THF/hexane and LiCl in THF. The vessel was
cooled to −60 °C in a constant-temperature bath controlled with a
coldfinger and prepared with fresh acetone. After a background
spectrum was recorded, neat allyl bromide was added with stirring. IR
spectra were recorded every 6 s with monitoring of the absorbance at
2
(18)
LiCl
CONCLUSIONS
■
Studies of dianionic Myers enolates certainly presented
challenges and surprises. The influence of aging on aggregate
structure and reactivity is profound and reinforces the notion
that enolates age remarkably slowly compared with other
organolithiums. The pseudoephedrine-derived Myers enolates
are slower to equilibrate than most, but they are by no means
−
1
1
610 cm over the course of the reaction.
8
MCV. The mathematical treatment for creating Job plots using
unique. Indeed, limited solution structural studies of enolates
20
Mathematica has been described previously. The specific case in
which octalithiated homoaggregates (formally tetramers) afford
hexalithiated heteroaggregates (trimers) required additional coding
as described in the Supporting Information.
to date suggest that most enolates, particularly the structurally
complex variants, undergo aggregate exchanges so slowly that
the unsuspecting user may be getting whipsawed by slow
aggregate equilibrations without realizing it. Functionalizing an
enolate under conditions in which aggregates have not
equilibrated may be constructive or destructive. Worse,
however, is when functionalizations of partially equilibrated
aggregates wreak havoc on attempts to develop rational models
to control and understand reactivity and selectivity.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.9b00328.
In some ways, the study of Myers enolates is about refining
protocols for characterizing complex organolithiums in
solution. We are positioning to move our gaze to Myers’s
second-generation enolates derived from the 1,2-diphenyl-
substituted amino ethanols. The new perspective might fill in
some details that eluded us in the current investigation.
Moreover, there are many dianionic enolates in which ancillary
lithium alkoxides, lithiated sulfonamides, or lithiated Boc-
amines are used in lieu of standard protecting groups. We are
optimistic that we now have the tools to probe structure−
reactivity relationships.
Spectroscopic, crystallographic, computational, and rate
data, as well as additional Job plots (PDF)
Process for NMR assignment, part 1 (MOV)
Process for NMR assignment, part 2 (MOV)
AUTHOR INFORMATION
Corresponding Author
dbc6@cornell.edu
■
*
ORCID
Samantha N. MacMillan: 0000-0001-6516-1823
David B. Collum: 0000-0001-6065-1655
EXPERIMENTAL SECTION
■
Reagents and Solvents. THF and toluene were distilled from
solutions containing sodium benzophenone ketyl. Pyridine was
distilled from solutions containing sodium benzophenone ketyl.
Notes
The authors declare no competing financial interest.
6
6
15
LDA, [ Li]LDA, and [ Li, N]LDA were prepared as described
ACKNOWLEDGMENTS
9
■
previously. Air- and moisture-sensitive materials were manipulated
We thank the National Institutes of Health (GM077167) for
support. We would like to thank Dr. Russell Algera for
mathematical assistance.
under argon using standard glovebox, vacuum line, and syringe
techniques. Myers enolate precursors were either purchased or
1
prepared as described previously. Several previously unreported
O
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Journal of the American Chemical Society
Article
kinetically stable, highly ordered, octameric form of lithium tert-
butoxide and its implications regarding aggregate formation. J. Am.
Chem. Soc. 2004, 126, 484. (c) Boyle, T. J.; Alam, T. M.; Peters, K. P.;
Rodriguez, M. A. Structural diversity of lithium neopentoxide
compounds. Inorg. Chem. 2001, 40, 6281.
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Structures of ß-Amino Ester Enolates: New Strategies Using the
Method of Continuous Variation. J. Am. Chem. Soc. 2008, 130, 17334.
(21) 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.
(22) Haq, I.; Lincoln, P.; Suh, D.; Norden, B.; Chowdhry, B. Z.;
Chaires, J. B. Interaction of. DELTA.- and. LAMBDA.-[Ru-
2+
(
phen) DPPZ] with DNA: A Calorimetric and Equilibrium Binding
2
Study. J. Am. Chem. Soc. 1995, 117, 4788.
(
23) Additional resonances appear at low THF concentrations.
(24) Reich, H. J. Role of Organolithium Aggregates and Mixed
Aggregates in Organolithium Mechanisms. Chem. Rev. 2013, 113,
130.
25) Allowing samples to stand at low temperature for weeks causes
7
(
no detectable increase in free enolate concentration, suggesting that
the failure to observe appreciable 4 is not the result of a suppressed
rate of exchange.
(26) In some cases, adding LiCl to hexalithiated heteroaggregates
causes considerable additional debris to appear, attesting to significant
formation of structurally complicated LiCl−enolate mixed aggregates.
(
27) Monitoring the influence of LiCl on the IR absorbance of
−
1
enolate 4 at 1640 cm revealed broadening of the peak with no
chemical shift changes.
(28) 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.
(29) LiBr is approximately 15-fold less effective at mediating the
alkylation. The low concentrations generated during the alkylation are
inconsequential.
(
30) We refer to (LiX) and (LiX) (LiX′) as a “homoaggregate”
n
m
n
and “heteroaggregate”, respectively, and reserve the term “mixed
aggregate” for (LiX) (LiY) .
m
n
(
(
31) Williard, P. G., unpublished.
32) For a discussion of the relationship of Li−N coupling and Li−
N bonding, see: Engelhardt, F.; Maaß, C.; Andrada, D. M.; Herbst-
Irmer, R.; Stalke, D. Benchmarking lithium amide versus amine
Q
DOI: 10.1021/jacs.9b00328
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX