High-throughput photocapture approach for reaction discovery

Article abstract of DOI:10.1073/pnas.2003347117

Modern organic reaction discovery and development relies on the rapid assessment of large arrays of hypothesis-driven experiments. The time-intensive nature of reaction analysis presents the greatest practical barrier for the execution of this iterative process that underpins the development of new bioactive agents. Toward addressing this critical bottleneck, we report herein a high-throughput analysis (HTA) method of reaction mixtures by photocapture on a 384-spot diazirine-terminated self-assembled monolayer, and selfassembled monolayers for matrix-assisted laser desorption/ionization mass spectrometry (SAMDI-MS) analysis. This analytical platform has been applied to the identification of a single-electron-promoted reductive coupling of acyl azolium species.

Full text of DOI:10.1073/pnas.2003347117

High-throughput photocapture approach for
reaction discovery
Alison A. Baylya, Benjamin R. McDonalda, Milan Mrksicha,1, and Karl A. Scheidta,1

aDepartment of Chemistry, Northwestern University, Evanston, IL 60208
Edited by Alexis T. Bell, University of California, Berkeley, CA, and approved April 29, 2020 (received for review February 21, 2020)
Modern organic reaction discovery and development relies on the
rapid assessment of large arrays of hypothesis-driven experiments.
The time-intensive nature of reaction analysis presents the greatest
practical barrier for the execution of this iterative process that un-
derpins the development of new bioactive agents. Toward address-
ing this critical bottleneck, we report herein a high-throughput
analysis (HTA) method of reaction mixtures by photocapture on a
384-spot diazirine-terminated self-assembled monolayer, and self-
assembled monolayers for matrix-assisted laser desorption/ionization
mass spectrometry (SAMDI-MS) analysis. This analytical platform has
been applied to the identification of a single-electron-promoted re-
ductive coupling of acyl azolium species.
highly valuable synthetic moieties (Fig. 1C). To efficiently evaluate
our hypothesis, we sought to screen different potential ketyl-type
radical precursors (10, 11), alkyl radical precursors (9, 12), Lewis
acid additives (13–15), and solvents. With a daunting array of
variables to investigate, we searched for methods to rapidly survey
this broad chemical space.
Typically, high-throughput screens are analyzed via conven-
tional methods such as ultraperformance liquid chromatography
mass spectrometry (UPLC-MS), or gas chromatography mass
spectrometry (GC-MS) (16–19) Although these approaches can
be effective, long analysis times limit screening efficiency. Spe-
cifically, most conventional UPLC-MS and GC-MS instruments
typically require 5–6 h and 10–12 h with conventional sample run
times, respectively, to process a 96-well sample plate.
high-throughput analysis self-assembled monolayers photocapture
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azoliums
To alleviate this analytical bottleneck, we looked to surface
analytical techniques, which in recent years have demonstrated
remarkable high-throughput capabilities (20–22). Specifically, the
surface analytical technique self-assembled monolayers for matrix-
assisted laser desorption/ionization mass spectrometry (SAM-
DI-MS) provides a general method for performing high-throughput
experiments (23, 24). Self-assembled monolayers (SAMs) are well-
defined structures formed by spontaneous assembly of functional-
ized alkanethiols on a gold-coated substrate (Fig. 2A) (25).
Monolayers can be functionalized with a broad range of molecular
groups and then treated with reagents (or enzymes) to yield prod-
ucts that are efficiently analyzed by SAMDI-MS (23, 24). Much of
our previous work has performed reactions directly on the
he development of new carbon–carbon bond forming reac-
T
tions underpins progress in the development of pharmaceuti-
cal and agrochemical agents. Over the past decade numerous
reports detailing new reactivity through N-heterocyclic carbene
(NHC) organocatalysis have been published (1) While these car-
bene catalysis manifolds have clearly been broadly explored, sig-
nificant opportunities remain. The traditional two-electron NHC
reactivity has defined the electrophile scope to mainly activated
π-acceptors such as carbonyl and imine-containing compounds.
Consequently, even straightforward reactions, such as alkylations,
remain largely unrealized. However, distinct single-electron strate-
gies with NHC catalysis and the associated acyl azolium interme-
diates could open new pathways by engaging reactive partners
outside the traditional π-acceptors mentioned above.
Significance
Redox NHC/azolium-based transformations have largely fo-
cused on oxidation of NHC intermediates, resulting in various
transformations of aldehydes to acids or esters (2–4). Early work
from the Scheidt laboratory achieved the oxidation of the Breslow
intermediate for the esterification of aldehydes (Fig. 1A) (2). In
another significant report, Boydston and coworkers demonstrated
that the Breslow intermediate can be oxidized under electro-
chemical conditions (Fig. 1B) (3). Studer and coworkers later
demonstrated that the electrochemical apparatus could be
substituted with a ruthenium catalyst and air (Fig. 1B) (4). Outside
of these oxidations of the Breslow intermediate, there are limited
examples of single-electron oxidative NHC/azolium manifolds in-
volving either homoenolates (5) or decarboxylative couplings (6, 7).
We hypothesized that a useful and unique radical intermediate
could be accessed via the single-electron reduction of acyl azo-
lium species (Fig. 1C). While the redox chemistry of azolium
salts has been investigated (8), the potential of acyl azolium salts
under these conditions has not. The reduction potential of azo-
liums spans a wide range (–1.3 to –2.2 V) (8). Importantly, these
values establish azoliums as reducible by commonly used pho-
toredox catalysts. Accordingly, the reduction of acylated variants
should be more facile. We envisioned that a photoredox catalyst
could reduce an acyl azolium, with the restoration of azolium
aromaticity driving the radical to carbonyl carbon. In conjunction
with this mesomeric stabilization, the flanking N-methyl groups
could provide steric shielding, leading to persistent ketyl radicals
(9) that would couple with benzyl radical species to form ketones,
Mass spectrometry (MS) has inspired powerful modes of reaction
discovery. Chemists often rely on MS methods, such as liquid-
chromatography MS and gas chromatography MS, to rapidly as-
sess hundreds of small-scale reactions. These chromatography-
based MS techniques are preferred as they typically provide
data consistent with scaled-up yields. Other MS approaches that
more rapidly analyze reactions frequently provide results in-
consistent with scaled-up yields. Herein we describe the devel-
opment of a high-throughput platform that overcomes the
analytical bottleneck presented by chromatography-based MS
techniques while retaining consistency with scaled-up results.
Our MS method, which combines diazirine photocapture and
self-assembled monolayers for desorption/ionization MS, en-
abled the analysis of ∼2,000 reactions in <2.5 h to realize an
intermolecular photoredox reaction.
Author contributions: A.A.B., B.R.M., M.M., and K.A.S. designed research; A.A.B. per-
formed research; M.M. and K.A.S. analyzed data; and A.A.B., M.M., and K.A.S. wrote
the paper.
The authors declare no competing interest.
This article is a PNAS Direct Submission.
Published under the PNAS license.
1To whom correspondence may be addressed. Email: milan.mrksich@northwestern.edu or
scheidt@northwestern.edu.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/
doi:10.1073/pnas.2003347117/-/DCSupplemental.
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Fig. 1. Approaches to single-electron chemistry with NHC intermediates. (A) Initial investigation into oxidation of Breslow intermediate. (B) Electrochemical
and metal-redox oxidation of NHC intermediates. (C) Reaction design plan for the reductive coupling of a ketyl radical with a benzyl (1°) radical to form
a ketone.
immobilized molecules for simplicity, but with the consequence that
reactivity on the monolayers did not always match the reactivity in
solution (26, 27).
Given the mechanistic duality in photoredox transformations
(32–35) (reductive or oxidative photocatalyst-quenching cycles),
we selected catalysts with a sufficiently broad redox potential
To circumvent this significant barrier while leveraging the effi- range. Therefore, the first catalyst selected was the versatile metal
cient analysis times (∼5 s per reaction), we implemented an ap-
proach where the reactions are performed in solution (using 96-well
plates), followed by pipetting the reaction mixtures onto a diazirine-
polypyridyl complex Ir(ppy)2(dtbppy)PF6 (PC 1) (E1/2 (Ir(III)
*/Ir(II)) = +0.66 V vs. SCE and E1/2 (Ir(III)*/Ir(IV)) = –0.96 V vs.
SCE) (36). The organophotocatalyst 4CzIPN (PC 2) was also se-
terminated SAM for UV-induced photocapture, and SAMDI-MS lected because we were interested in developing an inexpensive
analysis (Fig. 2A). This method, termed traceless immobilization
SAMDI-MS (TI-SAMDI-MS), has been applied as a tool to char-
acterize a P450 drug-metabolizing enzyme and to monitor a
Suzuki–Miyaura reaction (28); however, this method has never been
applied to high-throughput analysis (HTA) until this work.
and metal-free approach. Given that it is easily accessible syn-
thetically, and has a wide redox potential range (E1/2 PC*/PC−
=
+1.35 V vs. SCE and E1/2 PC−/PC = –1.21 V vs. SCE), 4CzIPN
was an ideal choice (37). Dimethylsulfoxide (DMSO) and MeCN
were selected as the two solvents to be tested as they have been
established as ideal solvents for charge-transfer reactions, and
therefore are commonly implemented in synthetic photoredox
chemistries (38).
Results and Discussion
To validate our approach, we demonstrated that the authentic
product could successfully immobilize to the diazirine monolayer
and that this molecule could be observed via SAMDI-MS at m/z
of 1,536 (Fig. 2B). With this process validated, we could in-
vestigate our hypothesized reactivity using the TI-SAMDI-MS
analysis method (Fig. 2C).
With these eight electrophilic acyl sources, five Lewis acids,
four Lewis acid loadings, three alkyl radical precursors, two
photocatalysts (Ir-based catalyst and an organic-based catalyst),
and two solvents, we set out to rapidly assess the various conditions
(Fig. 2D). Under inert atmosphere, 1,920 total reactions were set up
in 96-well photoredox plates and permitted to stir for 18 h on blue
Prior to our screen, we prepared two simple salts (E1 and E2)
to assess the reactivity of the acyl azolium NHC intermediate. We light emitting diode (LED) array pads (SI Appendix, Figs. S1 and
also incorporated six other electrophilic acyl sources (E3–E8) to
S2). We set up four 96-well plates at one time in glovebox (1 h),
determine necessity of the acyl azolium for the desired ketyl then permitted the reactions to run overnight (12 h). Upon com-
radical formation (Fig. 2D). Li and coworkers’ impressive visible- pletion, the unpurified and unprocessed mixtures were pipetted
light induced alkyl transfer report motivated us to incorporate the directly onto the diazirine monolayer with a multichannel pipetter
benzyl t-Bu Hantzsch ester (Bn HEH, E1/2 = +1.08 V vs. ) as a
(15-min/384-spot plate), UV-irradiated, and analyzed via SAMDI-
benzyl radical precursor substrate (Fig. 2D) (29). Additionally, MS (Fig. 2C). Postdata acquisition the spectra were analyzed via
Molander and coworkers’ alkyl silicate developments and appli-
cations inspired us to include the alkyl radical precursor ammo-
nium benzyl bis(catecholato)silicate (Bn Si, E1/2 = +0.70 V vs.
our Applied Biosystems Data Explorer Software.
Impressively, this method analyzed 1,920 reactions in ∼2.5 h
(see SI Appendix for experimental details and all screening re-
saturated calomel electrode [SCE]) (30). As commercially avail- sults). By this analysis, only six hits were found, constituting 0.3%
able carboxylic acids represent the ultimate radical precursor, we of the reactions screened (Fig. 3A). Hit reactions were designated
also included phenyl acetic acid (Bn-COOH) with an equimolar simply by whether the product peak (m/z of 1,536) was clear and
amount of base (Cs2CO3) as the third alkyl radical precursor (31). strong enough that it could not be confused with spectral noise.
The ubiquity of Lewis acids in ketyl radical formation necessitated We screened the limit of detection (LOD) and found that the
the investigation of various Lewis acids as additives (13–15).
product peak is not visible for yields of 30% or lower, and this
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Fig. 2. (A) Diazirine monolayer preparation. (B) Authentic product photocapture. (C) Screen workflow. (D) Screen parameters.
peak is clearly observed for yields of 40% or higher (SI Appendix,
Fig. S8). This LOD can be attributed to the photolyzed diazirine’s
highly reactive nature and its ability to insert readily into most
molecules. The diazirine monolayer effectively reacts completely
with the unpurified reaction mixture upon irradiation, and it is
(SI Appendix, Table S1). No false negatives were observed. Only
three sets of reaction conditions resulted in any product conver-
sion (see SI Appendix, Table S1 entries 1, 3, and 4); however, the
isolated yields were below the LOD (30–40% yield). These data
(Fig. 3 and SI Appendix, Table S1) establish that our screening
therefore unsurprising that several peaks are observed in addition to platform identifies valid hits as long as the yields are above the
the product insertion peak. Although the LOD is higher than ideal,
most reaction development programs would not pursue reactions
below this ∼30% yield. Consequently, this LOD can be viewed as
advantageous for robust reaction development. Efforts are un-
derway to evaluate this platform’s LOD for various reaction types.
The hit reactions were scaled to validate our findings and
determine if these provided suitable yields (Fig. 3). The hit-
limit of detection.
Li and coworkers’ mechanistic insights for light-induced pho-
toredox alkyl transfer with the Hantzsch ester (Bn HEH) heavily
informs our proposed reaction pathway in Fig. 4 (29). Addi-
tionally, TEMPO, a radical scavenger, was applied to the best hit
conditions and no product was observed, indicating that radical
intermediates are involved (SI Appendix, Fig. S9). To better
reaction yields ranged from moderate (40%) to high (70%). The understand the radical intermediate, cyclic voltammetry (CV)
higher yields were consistent with the higher intensity SAMDI-MS measurements were performed on the acyl benzimidazolium salt
peaks relative to other mixture components captured, and the (E1, Fig. 4B). Smooth, reversible electron transfer was observed
moderate yields corresponded to the lower relative intensity peaks for this substrate, indicating that the ketyl radical intermediate is
(Fig. 3B). Given the inconsistencies that often occur between stable until introduced to the benzyl radical for coupling (Fig.
matrix-assisted laser desorption/ionization (MALDI-MS) high-
throughput screen outputs and UPLC or scaled-up results (22,
4A). We were also pleased to observe that this reaction could be
applied with two other benzyl Hantzsch esters on hand (Br-Bn
24) we ran 10 different scaled-up reactions with nonhit conditions HEH and F-Bn HEH) with moderate yields (Fig. 4C). Efforts are
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Fig. 3. (A) Scaled-up hit reactions (0.1 mmol E1, 0.15 mmol Bn HEH). (B) Hit spectra for entries 1–6.
currently underway to investigate the scope of this reaction
further.
developed, previous MALDI-based high-throughput platforms
rely on ionizable functional groups built into the substrates in-
volved in the reactions investigated. Our ionizable functional
group (positively charged trimethyllysine) was built into the
monolayer; therefore, it does not interfere with the reactions, but
aids analysis. Moreover, given that we do not have to build our
reaction around ionizable groups since ours is incorporated in
Conclusion
In conclusion, this work demonstrates an HTA that allowed us to
efficiently and extensively evaluate an intermolecular carbon-
carbon bond forming reaction. With regard to the technology
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Fig. 4. (A) Proposed reaction pathway. (B) CV data for acyl benzimidazolium salt (E1). (C) Further examples with different Bn HEHs.
with EtOH, deionized ultrafiltered (DIUF) H2O, EtOH again, and dried under
a stream of N2. The photoaffinity linker solution (1 μM in Tris buffer, pH 8)
was applied to the plates (1 μL per spot) and warmed to 37 °C for 30 min.
Upon completion, the diazirine monolayer plate was washed with ethanol,
the SAM, TI-SAMDI-MS can be applied generally to any reaction.
What distinguishes this platform most from other matrix-assisted
laser desorption/ionization time of flight (MALDI-TOF)–based
high-throughput methods is that for our approach the screen
DIUF H2O, EtOH again, and dried under a stream of N2.
results consistently match the scaled-up or UPLC results. Such
reliability is especially significant given that inconsistency be-
tween screen results and UPLC or scaled-up results has been a
persistent problem with MALDI-MS analytical technology
(22). The TI-SAMDI-MS platform overcomes this inconsis-
tency issue while retaining the rapid analytics that MALDI-MS
provides.
Our screen clearly and rapidly established that the acyl ben-
zimidazolium salt (E1) was the superior ketyl radical precursor,
and that the Hantzsch ester (Bn HEH) was the optimal alkyl
radical precursor. This method also allowed us to identify spe-
cific nonobvious hit conditions (stoichiometric LiCl in MeCN)
to achieve 70% yields. This transformation discovered via TI-
SAMDI-MS is fundamental, and more broadly, the implications
of both the HTA and this chemical discovery are significant.
With nearly 2,000 reactions evaluated in ∼2.5 h, this semi-
quantitative analysis platform offers enormous value to reaction
development programs. Importantly, the photogenerated carbene
C-H insertion capture process enables the use of simple, non-
electronic or sterically biasing label, a benzylic methyl group. Fi-
nally, the radical–radical coupling discovered offers an intriguing
strategy to form carbon-carbon bonds.
Photoredox Reactions. Reactions were run in oven-dried glass vials in Para-
Dox 96-well-plate reactor blocks. The 96-well plates were brought into
the glovebox and the four reaction components were added as stock
solutions using micropipettes. The plates were sealed with screwed top
lids equipped with polytetrafluoroethylene (PTFE) gaskets, removed
from the glovebox, and placed on Lumidox 96-Well Blue LED arrays atop
a magnetic stirrer (500 rpm). After 18 h, the plates were unsealed for
analysis.
Reaction Photoimmobilization. Upon photoredox reaction completion, crude
reaction mixture aliquots (1 μL from four 96-well plates) were directly
pipetted onto the 384 diazirine monolayer spots. The 384-spot plate was
then placed inside a UVP Cross-linker 1000L and irradiated (10 min, λ=
365 nm).
SAMDI Data Analysis. After reaction photoimmobilization, the array plates
were washed (DIUF, then EtOH), treated with 2,4,6-trihydroxyacetophenone
matrix (20 mg/mL in acetone), and dried using a stream of N2. SAMDI arrays
were analyzed via MALDI-TOF MS using an AB Sciex 5800 series instrument
with 20-kV accelerating voltage in positive reflector mode (200 laser shots to
each spot). The obtained spectra were analyzed in an automated fashion
using the Applied Biosystems Data Explorer Software.
Data Availability. See SI Appendix for experimental details, spectra, and
screening results.
Materials and Methods
Diazirine SAMDI-Array Plate Preparation. Steel plates formatted to 384 wells
coated with titanium (5 nm) and patterned with gold (30 nm) were soaked (18
h) in an ethanolic solution of tri(ethylene glycol)-alkanethiol (EG3-alka-
nethiol) disulfide and a mixed disulfide of EG3-alkanethiol and maleimide-
terminated EG3-alkanethiol (0.1 mM). The arrays were subsequently washed
ACKNOWLEDGMENTS. We thank the US Defense Advanced Research
Projects Agency for generous support under the “Make-It” Award, 69461-
CH-DRP W911NF1610384 and National Institute of General Medical Sciences
(NIGMS) (R01GM073072, R01 GM131431, and F31GM116532 to B.R.M) for
financial support.
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