Microscopy Reveals: Impact of Lithium Salts on Elementary Steps Predicts Organozinc Reagent Synthesis and Structure

Article abstract of DOI:10.1021/jacs.9b02639

Lithium chloride is known to promote the direct insertion of metallic zinc powder into organohalides in the practical synthesis of organozinc reagents, but the reason for its special ability is poorly understood. Pioneering a combined approach of single-m

Full text of DOI:10.1021/jacs.9b02639

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Article
Microscopy Reveals: Impact of Lithium Salts on Elementary
Steps Predicts Organozinc Reagent Synthesis and Structure
Kristof Jess, Kazuhiro Kitagawa, Tristen K. S. Tagawa, and Suzanne A. Blum
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b02639 • Publication Date (Web): 04 Jun 2019
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Microscopy Reveals: Impact of Lithium Salts on Elementary Steps
Predicts Organozinc Reagent Synthesis and Structure
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Kristof Jess, Kazuhiro Kitagawa, Tristen K. S. Tagawa, and Suzanne A. Blum*
Department of Chemistry, University of California, Irvine, CA 92697-2025, USA
Supporting Information Placeholder
synthetically, though to our knowledge no others have been reported
with a single exception of LiBr.12 The reason for the limited
understanding is the inability of traditional analytical techniques to
probe reactions and small quantities of intermediates at the surface of
metals under reaction conditions.14
ABSTRACT: Lithium chloride is known to promote the direct
insertion of metallic zinc powder into organohalides in the practical
synthesis of organozinc reagents, but the reason for its special ability
is poorly understood. Pioneering a combined approach of single-metal-
particle fluorescence microscopy with 1H NMR spectroscopy, we
herein show that the effectiveness of different lithium salts towards
solubilizing intermediates on the surface of zinc metal establishes a
previously unknown reactivity correlation that predicts the propensity
of that salt to promote macroscale reagent synthesis and also predicts
the solution structure of the ultimate organozinc reagent. A salt-free
pathway is also identified. These observations of an organometallic
surface intermediate, its elementary-step reactivity, and the impact of
various synthetic conditions (salt, salt-free, temperature, stirring, time)
on its persistence, are uniquely available from the sensitivity and
spatial localization ability of the microscopy technique. These studies
unify previously disparate observations under a single unified
mechanistic framework. This framework enables the rational
prediction of salt effects on multiple steps in organozinc reagent
synthesis and reactivity. This is an early example of single-particle
microscopy characterization of elementary steps providing predictive
power in reaction development by gaining a sensitive and selective
spectral handle on an important intermediate, highlighting the role of
this next generation of analytical tools in the development of synthetic
chemistry.
Pioneering a combined single-metal-particle microscopy approach
that is sensitive enough to overcome these analytical limitations with
an 1H NMR spectroscopy approach,15 we here discover that the impact
of different salts on the solubilization of zinc surface intermediates
predicts both the rate acceleration in macroscale synthesis and the
solution structure of the ultimate organozinc reagent (Figure 1). The
fluorescence microscopy experiments provide information about
behavior of intermediates in elementary steps, whereas the NMR
spectroscopy experiments provide information about overall reaction
rate and product structure. The resulting new synthetic knowledge
provides a robust theoretical framework that unifies the understanding
of previously disparate multiple steps of the salt-mediated syntheses of
organozinc reagents, making the effect of lithium salts on multiple
steps predictable under one model.
Elementary Step:
Surface
Solubilization
Macroscale:
Conversion and
Structure
Predictive
Power
no salt,
LiOTf, LiF
RZnI
lower yield
Introduction. The finding by Knochel in 2006 that LiCl
substantially enhanced the rate of the direct insertion reaction of
organohalides to zinc metal1 led to a series of discoveries for the
practical preparation of organometallic reagents from metal powders.
The resulting reagents are useful, for example, as transmetallation
partners in Negishi cross-coupling reactions.2 Whereas only
organomagnesium (Grignard) reagents used to be widely accessible by
direct insertion of metals into organohalides,3,4 the organometallic
toolbox was expanded to zinc,1 indium,5–7 manganese,8 and aluminum9
through the addition of lithium chloride, sometimes in combination
with transition metal additives.10 Yet the mechanistic role of LiCl and
the impact of the presence of additives on the structure of the resulting
organozinc reagents remains poorly understood, limiting the expansion
of salt effects that promote oxidative addition to other metals. The
nature of the organometallic reagents that form from these reactions is
of the utmost importance to understand, as the presence of salts left
over is known to alter reactivity, often favorably.11,12 This observation
raises the possibility that other lithium salts13 would also be valuable
R
I
I
R
+
Zn
or
LiCl, LiBr, LiI
R2Zn
higher yield
intermediates
Zn
metal powder
enhanced
solubilization
Fluorescence
Microscopy
NMR
Spectroscopy
Figure 1. Synergistic approach.
Results and Discussion.
Single-Particle Fluorescence Microscopy Study. We recently
showed that fluorescence microscopy with sensitivity as high as to the
single-molecule level15–21 can characterize the presence and reactivity
of previously unknown oxidative addition intermediates on the surface
of zinc metal.22 In the experimental design, imaging agent 1 is
employed as a probe for oxidative addition surface reactivity. It
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consists of a BODIPY (boron dipyrromethene) unit that acts as a
addition of solid salts to different aliquots of zinc samples of 2 in THF.
spectator fluorophore, an oxidative addition reactive carbon–iodide
bond, and a butyl linker separating the BODIPY unit electronically and
sterically from the oxidative addition site (Figure 2, inset). Imaging
agent 1 in solution is not imaged because it is diffusing rapidly.
Oxidative addition to the zinc surface builds up surface intermediates,
depicted as 2. Previous control experiments16,22 are consistent with
assignment of 2 as the product of oxidative addition/direct insertion of
the surface zinc atoms into the C–I bonds of 1, upon which the imaging
agent becomes stationary and is imaged as bright green “hot spots” on
the surface of the previously dark zinc particles (Figure 2, top
schematic). As we showed previously, intermediate 2 is persistent in
the absence of a salt, but is solubilized rapidly upon addition of LiCl,
leaving behind dark zinc particles.22
All images are displayed at identical brightness/contrast settings to
allow direct comparison. An explanation of new regions is described
in Figure S1.
In the present study, we examined microscopy images of zinc
particles with bright green “hot spots” of 2 before and after addition of
different lithium salts LiX (X = F, Cl, Br, I; t = 90–150 s after addition;
Figure 2). In this way, it was possible to analytically study isolated
single elementary reaction steps. Specifically, the impact of different
lithium salts on the solubilization of oxidative addition surface
intermediates could be independently determined. Images from LiF
addition showed little to no difference in fluorescence intensities or
quantities of the “hot spots” before and after, meaning that LiF addition
did not noticeably solubilize intermediate 2 and remove it from the zinc
surface (Figure 2). This observation with LiF is the same as with LiOTf
from our previous studies.22 In contrast, directly after addition of LiCl,
LiBr, or LiI the green fluorescent spots disappeared or became
significantly dimmer across the entire sample (representative images,
Figure 2). Although it is impossible to find and study the exact same
particles before and after salt addition, the effect caused by salt
addition is fully consistent throughout the sample (see Supporting
Information for movies of whole sample). Based on our previous
studies,16,22 we interpret these findings as LiF and LiOTf being
inefficient at solubilizing organozinc intermediate 2, whereas LiCl,
LiBr, and LiI are efficient at solubilizing 2 to generate solution species
3∙LiX (Figure 2). Control experiments ruled out quenching of
fluorescence by lithium salts or adventitious water as the causes of
these results (see Supporting Information). These microscopy results
are significant because they identify important elementary steps in the
macroscale generation of organozinc reagents directly from zinc metal
powder and because they predict that LiBr12 and LiI are promising
candidates as additives for macroscale synthesis, whereas LiF and
LiOTf are not.
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I
+
Zn
N
=
I
I
F2B
1
N
20 h soak
then wash
oxidative addition
imaging agent,
THF
1
Zn
LiX
I
I
.
solution
LiX
Zn
.
solubilization
yes or no
3
species LiX
<3 min
Zn
oxidative addition
2
surface species
LiF:
no
solubilization
LiF
New
Region
The spatial and reactivity distribution of intermediate 2 in Figure 2
reflects the range of reactivity inherent to the synthetic system: The
same supplier and mesh of zinc particles were used as in the reported
synthetic procedure by Knochel,1 allowing detection of the
heterogeneity of reactivity germane to the “real” synthetic reaction.
These particles reacted differently, and even different locations on the
same particle were found to vary significantly in their reactivity, as
detected as a range of brightness and distribution of fluorescent
intermediate 2. This distribution is uniquely revealed by the sensitivity
and spatial resolution of the microscopy approach and is obscured by
a purely NMR spectroscopy approach that does not have sensitivity
sufficient for detection of 2 nor spatial/localization characterization
ability.
LiCl:
yes
solubilization
LiCl
New
Region
LiBr:
yes
solubilization
LiBr
New
We next investigated if there might be an alternative, salt-free
pathway accessible for solubilization of otherwise-persistent surface
intermediate 2 (Figure 3). For this experiment, a single sample of 2
was divided into portions for comparison, and treated with different
salt-free conditions that would mimic those present in a bulk synthetic
reaction:
Region
LiI:
yes
solubilization
LiI
New
Region
A first portion was soaked for 2 h in standing THF. This sample
showed little change and established continued persistence of 2. A
second portion was stirred for 2 h in THF. This sample showed a
middle extent of solubilization of 2, visible as a reduction in the
brightness and extent of coverage of bright green “hot spots” and more
completely dark particles with no detectible 2. Smaller particles of zinc
powder were generated through this stirring process, which were
distinctly observable post-stirring (see SI for movie and details). The
Figure 2. Top: Schematic of the fluorescence microscopy
experiments. Inset: Imaging agent for oxidative addition. Below:
Experimental fluorescence microscopy images show the effect of
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generation of these smaller particles suggested that stirring may assist
These observations of organometallic intermediate 2, its
elementary-step reactivity, and the impact of synthetic conditions (salt,
salt-free, temperature, stirring, time) on its persistence, are uniquely
available from the sensitivity and spatial localization ability of the
microscopy technique. This mechanistic information is fully obscured
by traditional analytical techniques such as NMR spectroscopy,
through which only the starting alkyl iodide and product organozinc
are observable, but not intermediate 2 nor its pathways, nor its apparent
rate-limiting behavior in the overall transformation. Instead,
fluorescence microscopy gains a sensitive and selective spectral handle
on an important intermediate that NMR spectroscopy could not
capture. These microscopy observations predicted bulk-scale synthetic
outcomes, as will next be described.
solubilization of 2 by breaking apart larger zinc particles into smaller
particles with higher surface area, or by removing the surface layer of
zinc by inter-particle friction (e.g., analogous to “sandblasting”). A
third portion was soaked for 2 h with heating at 100 oC. This sample
exhibited substantial solubilization of 2, as evidenced by widespread
reduction in the number and brightness of the green “hot spots” and
widespread presence of fully dark zinc particles without detectable 2.
The images in Figure 3 are representative single frames from movies
that examined the entire samples (see SI). Thus, a continuum of
persistence−solubilization occurred in salt-free systems, depending on
sample conditions analogous to those that might be present under bulk-
scale synthetic conditions.
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Together, these data are consistent with the accessibility of a higher-
barrier solubilization of intermediate 2 under salt-free synthetic
conditions or in the presence of an ineffective salt. This pathway was
notably slower than that assisted by LiCl, LiBr, and LiI (for
comparison, <3 min, ambient temperature, Figure 2). Therefore, a
slower salt-free pathway should also be accessible in the synthetic
reaction for formation of alkylzinc reagents with sufficient heating or
stirring.
1H NMR Spectroscopy Study. To investigate if the trend observed
by fluorescence microscopy predicted which salts would be effective
in accelerating the rate of synthesis of organozinc reagents, we studied
the conversion of (2-iodoethyl)benzene (4) to its corresponding
organozinc species 5 by 1H NMR spectroscopy (Table 1). The
deliberately ambiguous notation used by Knochel, “5∙LiX” in Table 1,
avoids implying a structure.1,23 Substrate 4 was reacted with 1.4 equiv
of zinc and 1 equiv of LiX; a control experiment without any salt
additive was also conducted. In these experiments, it is evident that
there are two sets of conditions: experiments with LiF, LiOTf, or
without any salt gave lower conversions (56–62%: Set 1), whereas
experiments with LiCl, LiBr, and LiI gave full conversion (Set 2).
These outcomes on the macroscale correlate with the reactivity trend
observed by fluorescence microscopy in that they sort the salts into the
same two sets. This observation provides compelling support for the
conclusion that the ability of a salt to solubilize surface intermediates
is the mechanistic cause of the rate enhancement observed in the
macroscale synthetic reaction.
Salt-Free
Pathway
Zn
I
I
3
solution species
2 h, THF
Zn
conditions
Zn
oxidative addition
2
surface species
soaking,
r.t.
Table 1. Salt Effect Observed on Intermediates by
Fluorescence Microscopy Predicts Macroscale Synthesis
Effects.
Zn, (LiX)
Mesitylene, THF-d8
.
ZnI( LiX)
I




stirring,
r.t.
1500 rpm, 2 h
4
5
or
(X = F, Cl, Br, I, OTf)
.
5
LiX
NMR
Solubilization of 2
Salt
in Elementary Stepa
Conversion [%]
1
directly after soak
and wash
No salt
LiOTf
LiF
57
62
--
soaking,
100 °C
no
Set 1
Set 2
56
no
LiCl
LiBr
LiI
99
yes
yes
yes
99
Figure 3. Top: Schematic of the fluorescence microscopy
experiments. Below: Fluorescence microscopy images showing higher
barrier salt-free solubilization. All images are displayed at identical
brightness/contrast settings to allow direct comparison.
>99
a See Figure 2. LiOTF data from previous experiments.22
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Figure 4. 1H NMR spectra (THF-d8, 500 MHz, 300 K) for the reaction of (2-iodoethyl)benzene (4) with zinc as described in Table 1. Letter α
denotes signals for CH2–I in 4 or CH2–Zn in products 5 or 5∙LiX and letter β denotes signals for CH2–Ph.
1
Next, a closer examination of the H NMR spectroscopy data
revealed that the two sets of salts identified in the microscopy
experiments generated two sets of structurally different organozinc
reagents in solution (Figure 4).
Figure 5 shows expansions of the α proton regions. The signals
from organozinc compounds derived from LiCl, LiBr, and LiI are
prominent second-order AA'XX' coupling patterns, providing
strong evidence for a shared conformational30 structural feature.
Set 1. Organozinc compounds formed in the presence of LiF,
LiOTf, or no salt, exhibit α methylene protons further downfield,
at 0.53 ppm, independent of the presence or nature of lithium salts
in this set. This result indicates that the identical organozinc
product is formed in all three cases, assigned as monomeric RZnI24–
In contrast, the signals arising from the organozinc compound
generated in the presence of LiF, LiOTf, or no salt did not display
this pattern. These signals likely all arise from the identical
compound, RZnI24. 7Li NMR spectroscopy data is further
consistent with this assignment (see Supporting Information for
details).
26
.
Set 2. Organozinc compounds formed in the presence of LiCl,
LiBr, and LiI exhibit α methylene protons at 0.38−0.39 ppm,
almost independent of the nature of the lithium salts within this set.
This independence suggests that these samples likely contain the
same major equilibrium structure, but a different structure than that
formed in Set 1. We previously detected [RZnX2]- by negative
ionization ESI-MS in reactions of 1 with Zn in the presence of
LiCl,16 similar to the types of complexes observed by
These 1H NMR spectroscopy data provide compelling evidence
that the two classes of lithium salts, identified first by microscopy
to produce reactivity differences on solubilization of intermediates
from the zinc surface, produce two different macroscale rate
classes, and two different structural classes of organozinc reagents
in solution. This correlation was previously unknown, and thus
provides a new conclusion about reactivity.
1
Koszinowski.27,28 In previous studies by Organ using H NMR
spectroscopy and ESI-MS, it was suggested that for the LiBr
assisted organozinc formation in THF, a plausible product is the
neutral diorganozinc compound R2Zn (from Schlenk equilibrium
with mass balance of Li[ZnBr3], eq 1).29 In accordance, our own 1H
NMR spectral data presents compelling evidence that the same
organozinc structure is formed regardless of the nature of X in this
set; thus, R2Zn appears to be the main organozinc equilibrium
structure in all cases within salt Set 2.
Schlenk equilibrium
(1)
2 RZnX + LiX
R2Zn + Li[ZnX3]
THF
favored side
no LiX or OTf, F
favored side
Cl, Br, I
Distinct coupling patterns further confirm the existence of two
different sets of solution structures for these organozinc reagents.
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Figure 5. 1H NMR spectroscopy expansion of the methylene
powders with salt additives, a broadly desirable reaction class in
synthetic chemistry that has been previously limited by its
empirical development.
1
2
3
groups H-α on organozinc 5 (∙LiX). a In the case of LiCl and LiBr
the expansion from Figure 4 showed artefacts from misadjusted
shim, therefore the corresponding expansions from a different set
of experiments are shown here for clarity.
4
5
6
7
8
9
Unified Theoretical and Predictive Model. The propensity of
the anion X to coordinate to zinc to form a zincate is the crucial
difference for solubilization of the surface intermediate, which
causes accelerated organozinc reagent formation. The same
propensity dictates the final solution structure of the reagent formed
after equilibrium is established, with a strong binding X shifting the
Schlenk equilibrium and a weak binding X not shifting the Schlenk
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
Experimental details, replicate microscopy data, movies, H/7Li
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NMR data, details of control experiments (PDF, AVI).
equilibrium (eq 1). Figure
6
shows
a
depiction of
AUTHOR INFORMATION
intermediates/transition states, involving the critical coordination
of the second halide of Cl, Br, and I to zinc as part of the
solubilization step (Set 2). This zincate is apparently more soluble
than the neutral organozinc complex in THF, leading to its faster
dissolution from the surface. Plausibly this enhanced solubility
arises from the known coordination of lithium cations by THF,
resulting in a nonequilibrium complex of (THF)nLi[RZnX2], which
is responsible for the release of the organozinc species from the
surface. This complex is then available to equilibrate in solution to
R2Zn + Li[ZnX3].
Corresponding Author
*blums@uci.edu
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank the National Science Foundation (CHE-1464959) and the
University of California, Irvine (UCI), for funding. K. J. thanks the
German Research Foundation (DFG) for a fellowship (JE 886/1-1)
and K. K. thanks the Japan Society for the Promotion of Science
for a fellowship (JP15J03538).
For the cases with LiF, LiOTf, and no salt (Set 1), another
mechanism of solubilization occurs, which does not involve LiX.
This solubilization pathway is evident in Figure 3. In the case of
LiF, its lower solubility in THF (0.1 mM at 24 °C)31 indicates that
strong LiF bonds plausibly disfavour formation of Li[RZnIF]. The
weakly coordinating nature of triflate plausibly reduces its
propensity for binding to zinc. Thus, in the absence of sufficient
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Elementary Step:
Surface
Solubilization
Macroscale:
Conversion and
Structure
Predictive
Power
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7
no salt,
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LiOTf, LiF
RZnI
lower yield
R
I
I
R
+
Zn
or
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LiCl, LiBr, LiI
R2Zn
higher yield
intermediates
Zn
metal powder
enhanced
solubilization
Fluorescence
Microscopy
NMR
Spectroscopy
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