Mechanism of an Elusive Solvent Effect in Organozinc Reagent Synthesis

Article abstract of DOI:10.1002/chem.202002214

Solvent effects are often difficult to understand in cases where reaction intermediates, and thus their differential behavior in different solvents, are not directly observable by traditional ensemble analytical techniques. Herein, the sensitivity of single-particle fluorescence microscopy uniquely enables direct observation of organozinc intermediates and solvent effects on their build-up and persistence. When combined with NMR spectroscopy, these imaging data pinpoint the previously elusive mechanistic origin of solvent effects in the synthesis of widely used organozinc reagents. These findings characterize the acceleration of oxidative addition of the starting organoiodide to the surface of zinc metal in DMSO relative to THF, but once formed, surface intermediates display similar persistence in either solvent. The current studies are the first demonstration of a highly sensitive, single-particle fluorescence microscopy technique to pinpoint otherwise elusive solvent effects in synthetic chemistry.

Full text of DOI:10.1002/chem.202002214

Accepted Article
Accepted Article
Title: Mechanism of an Elusive Solvent Effect in Organozinc Reagent
Synthesis
Authors: Erin M. Hanada, Kristof Jess, and Suzanne A. Blum
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Chem. Eur. J. 10.1002/chem.202002214
Link to VoR: https://doi.org/10.1002/chem.202002214
01/2020

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Mechanism of an Elusive Solvent Effect in Organozinc Reagent
Synthesis
Erin M. Hanada,+a Kristof Jess,+a and Suzanne A. Bluma*
[a]
[+]
Prof. S. A. Blum, E. M. Hanada, Dr. K. Jess
Department of Chemistry
University of California, Irvine
Irvine, CA 92697−2025, USA
E-mail: blums@uci.edu
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of the document.
Abstract: Solvent effects are often difficult to understand in cases
where reaction intermediates, and thus their differential behaviour in
different solvents, are not directly observable by traditional ensemble
analytical techniques. Herein, the sensitivity of single-particle
fluorescence microscopy uniquely enables direct observation of
organozinc intermediates and solvent effects on their build-up and
persistence. When combined with NMR spectroscopy, these imaging
data pinpoint the previously elusive mechanistic origin of solvent
effects in the synthesis of widely used organozinc reagents. These
findings characterize the acceleration of oxidative addition of the
starting organoiodide to the surface of zinc metal in DMSO relative to
THF, but once formed, surface intermediates display similar
persistence in either solvent. The current studies are the first
demonstration of a highly sensitive, single-particle fluorescence
microscopy technique to pinpoint otherwise elusive solvent effects in
synthetic chemistry.
a. Traditional Ensemble Technique
o
o
s
o
o
s
s
o
o
o
o
o
s
o
o
s
?
observable
starting material
unobservable
intermediate
observable
product
Single-Molecule and -Particle
Fluorescence Microscopy
b.
R
I
ZnI
I
R
R
Hypothesis 2
Hypothesis 1
+
Zn
+
Solvent effects are powerful tools for enhancing chemical
reaction rates and selectivities.[1–4] Yet, the mechanistic basis[5] of
these effects can be elusive. For this reason, synthetic methods
are often optimized through purely empirical solvent screening
approaches. These approaches typically provide insufficient
mechanistic understanding for underpinning future reaction
design. Fundamentally, the lack of understanding in these cases
arises from the inability of traditional ensemble analytical
techniques to observe low quantities of intermediates due to
insufficient sensitivity or dynamic range. Thus, the effect of
solvent on the generation and persistence of these intermediates
cannot be determined by direct observation (Scheme 1a). The
formation of organozinc reagents from zinc metal and
organohalides in different solvents is one of these cases. The
reaction has been the focus of study for over 50 years, due to the
synthetic importance of these compounds in Negishi cross-
coupling and other C−C bond forming reactions.[6–11] Initially, polar
aprotic solvents (e.g., mixtures with DMSO[12,13], or DMF[7,14]) were
required. This requirement was circumvented later by Knochel,
who showed that LiCl salt additive enabled direct insertion in
THF.[15] Yet, the origin of these solvent effects remains poorly
understood. Determination of the origin would provide guiding
principles for expanding practical direct insertion chemistry to
diverse metal powders, a desirable but currently limited area of
synthetic chemistry.
DMSO
accelerates
oxidative
addition
DMSO
accelerates
solubilization
Zn
Zn
metal powder
observable
intermediate
Scheme 1. (a) Schematic of the broader mechanistic problem with traditional
ensemble analytical techniques. (b) Two mechanistic hypotheses for solvent
effects in organozinc synthesis.
Harnessing single-particle fluorescence microscopy with up to
single-molecule sensitivity, we now combine bench-scale NMR
spectroscopy kinetics and structural studies with imaging studies,
enabling correlation of macroscale reaction solvent effects with
microscale effects on intermediates. We previously detected
organozinc surface intermediates from the combination of zinc
metal with organoiodides. Those prior studies demonstrated a
mechanism of reaction acceleration of the salt additive, LiCl, in
THF as solubilization of intermediates from the surface of zinc
after oxidative addition.[16–18] It remained unanswered, then, if the
two known synthetic routes to organozinc reagents from zinc
metal (e.g., LiCl in THF, or polar aprotic solvent) function by the
same mechanism (i.e., increase solubility of the surface
organozinc intermediate, Hypothesis 2, Scheme 1b), or if the two
routes function by different mechanisms (e.g., LiCl in THF
accelerates
1
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Bench-Scale Organozinc Synthesis
Examination of Hypothesis 1
1. solvent, 25 °C
30 min soak
a.
c.
I
unobservable
intermediates
by NMR
I
ZnI
I
solvent
Zn
+
+
Zn
Zn
25 °C
1500 rpm
2. THF rinse
3. imaged in hexanes
1
2
3
4
1H NMR Yield DMSO-d6 or THF-d8
observable
intermediate
b.
d.
DMSO
100
80
60
40
20
0
I
AvgTHF
AvgDMSO
THF fit
=
N
N
e.
B
THF
F
F
DMSO fit
3
0
50
100
150
200
250
time (min)
Scheme 2. (a) Bench-scale chemical reaction monitored by NMR spectroscopy. (b) NMR spectroscopy yield relative to internal standard vs time, in DMSO-d6 (red)
and THF-d8 (blue). (c) Chemical reaction for fluorescence microscopy experiments. (d) Representative zinc particle in DMSO after 30 min, fluorescence microscopy
image. (e) Representative zinc particle in THF after 30 min, fluorescence microscopy image. Green “hot spots” of observable intermediate 4, and the full chemical
structure of imaging agent 3. Images d and e are displayed at the same brightness/contrast settings for direct comparison.
solubilization of intermediates, but polar aprotic solvents
accelerate oxidative addition, Hypothesis 1). Previous
experimental data, obtained through indirect stereochemical and
radical-clock experiments, strongly suggest that oxidative addition
of alkyl iodides to zinc proceeds through single-electron transfer
pathways.[19] The resulting transient charged intermediates would
plausibly be stabilized by polar solvents, lending credence to a
mechanistic possibility wherein polar solvents could act through
acceleration of oxidative addition.[20]
removes the inactive surface layer but which generates additional
variability during handling.[16–18] 1H NMR spectroscopy kinetics
were measured in triplicate in each solvent relative to an internal
standard (Scheme 2b).
Consistent with the heterogeneous nature of the reaction,
replicate runs showed some variation in numerical yields at each
time point. Nevertheless, clear, reproducible trends were
observed, which were significantly larger than the variation in the
measurement: 1) Formation of 2, identifiable by the substantial
upfield shift of its a-zinc methylene protons, was significantly
faster in DMSO-d6 than in THF-d8. After 30 min, the 1H NMR
spectra indicate nearly complete conversion in DMSO-d6, but only
3% conversion in THF-d8. The reaction in THF-d8 reaches 96%
yield only after 4 h (Scheme 2b). 2) Regardless of solvent, only
starting material 1 and product 2 are observable by 1H NMR
spectroscopy. No reaction intermediates are observable. Thus,
the solvent effect cannot be pinned to impact on a specific
reaction step or intermediate by NMR spectroscopy alone. This
unobservability of intermediates highlights the broader
mechanistic challenge; and 3) An induction period is evident in
THF-d8 but not in DMSO-d6.
Given the range of reported literature procedures in
organozinc reagent synthesis, with variables including reaction
stir rate, zinc particle size and supplier, and presence or absence
of a zinc pretreatment step, a robust comparison of bench-scale
synthetic reaction rates in DMSO and THF was not readily
available in the existing literature. NMR spectroscopy kinetics
comparing synthetic conditions were therefore performed in-
house. Specifically, the kinetics of the reaction of 2-
iodoethylbenzene (1, [100 mM]) and zinc powder in DMSO-d6 and
separately in THF-d8, to generate organozinc 2 were examined
(Scheme 2a). To simplify this direct comparison, we opted to
avoid a pretreatment step with TMSCl or iodine[7], which partially
2
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Scheme 3. Fluorescence microscopy: (a) Relative persistence of oxidative addition intermediate 4 in DMSO at ambient temperature. (b) Activation of Zn surface
(shown as Zn*) by stirring in THF, consistent with removal of a surface oxide layer being the source of the induction period observed in THF in Scheme 2b. (c) No
activation of Zn surface with DMSO upon presoaking.
distributions of the bright green “hot spots” of fluorescence on zinc
With a robust understanding of the solvent effect on the
reaction overall, we next investigated the impact of solvent on the
build-up and persistence of organozinc surface intermediates by
single-particle fluorescence microscopy. These experiments
harnessed organohalide reagents with sensitive and
chemoselective spectral handles to observe organozinc surface
intermediates by fluorescence microscopy that were not
observable by NMR spectroscopy. An alkyl iodide tagged with a
green spectator boron dipyrromethene (BODIPY) fluorophore, 3
(2 mM), reacted with zinc metal to form observable surface
oxidative addition intermediate 4 (Scheme 2c).[16–18] Intermediate
4 was characterized as bright green “hot spots” on the surface of
otherwise dark zinc particles. In THF, these intermediates are
persistent,[16–18] unless the sample is treated with lithium salts,
heating, or strong stirring.[18] The brightness on a particle in these
fluorescence microscopy images is a measure of the quantity of
4. Thus, through this imaging technique, the impact solvents have
on the build-up and persistence of intermediate 4 could now be
characterized by direct observation of changes in quantity of 4.
particles in DMSO. The images in Figure 2d,e show two
representative zinc particles from these samples.
Together, these data are consistent with Hypothesis 1: DMSO
leads to faster generation of oxidative addition surface
intermediate 4 compared to THF, providing a step-specific
mechanistic explanation for the higher efficiency of DMSO
previously observed in macroscale synthesis.
Control Experiments. In order to determine if the fluorescent
spots on the DMSO-soaked particles in Scheme 2d were indeed
oxidative addition intermediate 4[16–18], control experiments were
conducted with the same conditions but employing different
fluorophores. These control fluorophores were identical except
they had either no carbon−iodide bond, and therefore could not
undergo oxidative addition, or a less reactive sp2 carbon−iodide
bond, which would undergo oxidative addition more slowly (see
SI). All control samples showed little fluorescence compared to
the samples treated with 3 (see SI).[17]
Examination of Hypothesis 2: DMSO accelerates
solubilization of surface intermediate. The operation of the
mechanism in Hypothesis 1 does not, on its own, exclude the
concurrent operation of the mechanism in Hypothesis 2. To
examine Hypothesis 2, the persistence of surface intermediate 4
in these two solvents was compared. In both DMSO and THF,
intermediate 4 was largely persistent upon standing or stirring for
2 h at ambient temperature (Scheme 3a; THF established
previously[18]). Thus, there is not a significant solvent effect on
solubilization of the surface intermediate and the mechanism in
Hypothesis 2 is not co-implicated.
Examination of Hypothesis 1: DMSO accelerates oxidative
addition. The rate of build-up of intermediate 4 in DMSO and in
THF was examined by fluorescence microscopy. Two parallel
samples of zinc powder were soaked in solutions of oxidative
addition imaging agent 3 in DMSO or THF for 30 min (Scheme
2c). Both zinc samples were then rinsed and transferred into
hexanes, an inert solvent, to prevent potential data convolution by
differential solubilization of 4 during imaging. Reactions in DMSO
and THF were each performed in triplicate to characterize the
range of brightness inherent to the heterogeneous nature of the
reaction system (see SI for triplicate data).
These data therefore indicate two different and complimentary
mechanisms for the reported rate accelerations of organozinc
reagent generation in the two synthetic literature preparations:
polar solvent accelerates oxidative addition whereas LiCl in THF
accelerates solubilization.
Single-particle imaging enabled direct comparison between
the two samples. Outcomes for samples reacted in DMSO and
THF starkly contrasted: DMSO produced substantially greater
build-up of oxidative addition surface intermediate 4 than did THF,
as observed by the significantly higher intensities and fuller spatial
3
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during vigorous stirring to expose the reactive zinc surface toward
oxidative addition. These results provide a clearer mechanistic
basis for the high efficiency of ultrasonic treatment of zinc towards
oxidative addition substrates,[26,27] and as such, are potentially
important for additional heterogeneous reactions with metals that
may be activated towards reaction intermediate generation by
vigorous mechanical processes.
Coordination environment of the organozinc reagent formed
in DMSO. The coordination environment of the organozinc
species in the two different solvents was next examined. The
ligand coordination environment around organozinc reagents
formed through these direct insertion reactions is of the utmost
importance, as it dictates the downstream reactivity of the reagent
(e.g., in metalation[21] and Negishi cross-coupling reactions[6,10]).
DMSO, for example, has been crystallographically characterized
in O-bound Zn(II) complexes.[22]
Second, preactivation by dissolution of the inactive surface
layer in DMSO was examined (Scheme 3c). Presoaking the zinc
in DMSO without stirring (which avoided a convoluting vigorous
mechanical processes) followed by reaction in THF did not lead
to enhanced intermediate formation, which ruled out fast chemical
or solubilization removal of the inactive surface layer by DMSO.
This observation is consistent instead with the idea that, in DMSO,
the more rapid chemical process of oxidative addition causes
etching that is sufficiently rapid itself to expose additional reactive
zinc surface, leading to the absence of an observable induction
period in DMSO.
To explore the coordination environment in DMSO, a
stoichiometric amount of DMSO was added into a THF-d8 solution
of 2 (eq 1). Monoorganozinc iodides like 2 have been previously
characterized as monomeric in THF.[18,23] New compound 5 is
structurally similar and therefore also likely to be monomeric. The
resulting NMR spectrum showed an upfield shift in the product
peaks of the organozinc[3] (from 0.53 to 0.44 ppm) and a downfield
shift in the product DMSO peak (from 2.46 to 2.65 ppm),
consistent with DMSO complexation to form 5. Mass spectrometry
data from this sample showed evidence for ions derived from both
2 and 5 (eq 1).
In conclusion, single-particle fluorescence data combined with
NMR spectroscopy data characterized solvent effects on overall
reaction rates and induction periods, pinpointed the mechanistic
origin of rate acceleration in DMSO to oxidative addition
(Hypothesis 1) and not to solubilization (Hypothesis 2), and
identified solvent-dependent differences in coordination
environment of the generated organozinc reagents. These data
indicate two different and complimentary mechanisms for the rate
accelerations of organozinc reagent generation in the two
reported synthetic literature preparations: polar solvent
accelerates oxidative addition whereas adding LiCl in THF[15]
accelerates solubilization[16]. Such mechanistic information aids in
the design and optimization of desirable direct insertion chemistry
to metal powders. This advance in sensitive imaging technology
opens avenues for obtaining further elusive mechanistic solvent
effect information, enabling predictive reaction design.
O
S
2.65 ppm
2.46 ppm
I
ZnI
Zn
S
(1 equiv)
O
(1)
0.44 ppm
0.53 ppm
THF-d8
2
5
[PhCH2CH2ZnI2]
[PhCH2CH2Zn(DMSO)]
m/z = 422.8
m/z = 247.0
A continued shift of these resonances upon titration with a second
equivalent of DMSO was consistent with an equilibrium between
complexes 2 and 5 (product organozinc to 0.39 ppm, and product
DMSO to 2.60 ppm). This complexation suggests solvent-
coordinated structures similar to 5 as the major coordination
environment in neat and mixtures of DMSO relevant to
applications in organic synthesis.[12,13] These data establish that
the coordination environment of 5, and plausibly also of the
surface intermediate 4 by extension (potential coordination shown
in grey in Scheme 3a), are different in DMSO than in THF.
Acknowledgements
We thank the National Institutes of Health (R01GM131147)
and the University of California, Irvine (UCI), for funding. K.J.
thanks the German Research Foundation (DFG) for a fellowship
(JE 886/1-1). We thank Ms. Hannah F. Peacock for replicate
experiments, and Mr. Tristen K. S. Tagawa for development of
hexane imaging protocol.
The possibility that the alkyl iodide substrate is first activated
in solution by nucleophilic displacement of iodide by DMSO,
creating a potentially faster reacting oxidative addition partner,
was considered. Such intermediates are proposed at elevated
temperatures (150 °C) in Kornblum oxidations of primary alkyl
iodides to aldehydes by DMSO solvent.[24] As the potential
solution intermediate was not observable at ambient temperature
in THF or DMSO by 1H NMR spectroscopy, however, this
possibility could not currently be examined further.
Keywords: Organozinc • Solvent Effect • Single-particle
fluorescence microscopy • Mechanism • Oxidative addition
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[3]
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The mechanistic origin of the solvent-dependent induction
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“preactivation” of the zinc was examined by both mechanical and
chemical methods. In the first experiment, zinc powder was stirred
vigorously in THF in the absence of other reagents, and then
treated with a solution of imaging agent 3. The resulting
mechanically “preactivated” particles of zinc displayed
significantly enhanced build-up of intermediate 4 (compare
images in Scheme 2e with Scheme 3b). These data are
consistent with the induction period in THF arising from the time
needed for mechanical etching of the inactive surface layer[25]
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Entry for the Table of Contents
Solvent Effects
Traditional Ensemble
Techniques
Single-Particle
Microscopy
o
o
s
o
o
s
s
o
o
o
o
o
s
o
o
s
unobservable
?
observable
Sensitive single-particle fluorescence microscopy experiments enable understanding solvent effects by direct observation of
previously “unobservable” organometallic surface intermediates. Combination of this microscopy technology with 1H NMR
spectroscopy characterizes the solvent effect on the synthesis of widely used organozinc reagents.
6
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