Coupling Photocatalysis and Substitution Chemistry to Expand and Normalize Redox-Active Halides

Article abstract of DOI:10.1021/acs.orglett.1c00173

Photocatalysis can generate radicals in a controlled fashion and has become an important synthetic strategy. However, limitations due to the reducibility of alkyl halides prevent their broader implementation. Herein we explore the use of nucleophiles that can substitute the halide and serve as an electron capture motif that normalize the variable redox potentials across substrates. When used with photocatalysis, bench-stable, commercially available collidinium salts prove to be excellent radical precursors with a broad scope.

Full text of DOI:10.1021/acs.orglett.1c00173

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Letter
Coupling Photocatalysis and Substitution Chemistry to Expand and
Normalize Redox-Active Halides
Manjula D. Rathnayake and Jimmie D. Weaver, III*
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ABSTRACT: Photocatalysis can generate radicals in a controlled fashion and
has become an important synthetic strategy. However, limitations due to the
reducibility of alkyl halides prevent their broader implementation. Herein we
explore the use of nucleophiles that can substitute the halide and serve as an
electron capture motif that normalize the variable redox potentials across
substrates. When used with photocatalysis, bench-stable, commercially available
collidinium salts prove to be excellent radical precursors with a broad scope.
he use of visible light to drive reactions has the potential to
be energy-efficient and green and can reveal new
catalyst structure aimed at pushing the reduction limits has been
pursued by several groups31−34 (Scheme 1a). Alternatively,
Leonori recently proposed the use of α-amino radicals to
facilitate halogen transfer (Scheme 1b).35 More relevant to this
work, Melchiorre identified a clever system that capitalizes on
the electrophilicity of alkyl halides to be displaced by a
nucleophilic chromophore (Scheme 1c).36 Upon displacement
of the halide with a nucleophilic chromophore, the alkyl
substrate becomes photoactive and upon absorption of a photon
undergoes homolysis of the inherently weak C−S bond. One
potential liability of this conceptually elegant approach is the
inherent coupling of the nucleophilic and chromophoric
capacities of the catalyst, which may limit both the scope of
reactions and the range of mechanistically diverse reactions that
would be possible if these two aspects of the catalysts operated
independently.
Thus, we set out to develop a conceptually related idea
(Scheme 1d)37−40 that capitalized on the electrophilicity of alkyl
halides but decoupled the photon-absorbing aspects of the
catalyst from its nucleophilic aspects. Our objective was to
identify a nucleophile that upon addition to the alkyl halide
would serve as the electron-capturing component where the
halide failed and ultimately would level the substrate reduction
potentials. Thus, we began our studies by exploring a Giese-type
T
mechanistic possibilities that enable synthesis.1−4 Often central
to these methods is the controlled generation of radicals, which
are the critical reactive intermediates5−13 whose formation is
enabled and governed by absorption of a photon by the
photocatalyst.14 Some substrates that can be reductively
activated by single electron transfer (SET) include aryl halides15
and pseudohalides.16−20 Reaction is possible because of the
relatively low-lying unoccupied π* orbitals of the aromatic
system into which an electron is transferred. En route to radical
formation, intramolecular ET to the C−X σ* orbital takes place,
allowing the critical mesolytic fragmentation that yields the
halide ion and carbon-centered radical.21−23 The rate of this
intramolecular ET is dependent on a number of factors,
including the energy of the π* orbitals and the electronic
overlap with the fragmenting groups.22,24−30 Practically speak-
ing, useful rates of radical anion fragmentation are observed for
ipso-substituted halides and α-halo species but decrease with
greater structural separation, representing a real mechanistic
limitation of the radical anion fragmentation mechanism. This
sensitivity to structure is particularly revealing in the case of
benzylic halides, in which the rate of fragmentation becomes
highly dependent on the structure and functional groups
attached to the aromatic component, resulting in significant
variation in the reduction potential and the nature of the orbitals
involved.26,27 In general, the substantial variation in reduction
potential of the substrates (Scheme 1d) prevents the develop-
ment of broadly applicable methodology.
Received: January 16, 2021
Published: February 26, 2021
Recently, several diverse strategies have been explored to
engage such aliphatic halides that would otherwise be hard to
directly engage photocatalytically. Evolution of the photo-
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© 2021 American Chemical Society
Org. Lett. 2021, 23, 2036−2041
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Letter
(see the Supporting Information). In contrast, pyridinium 1d,
which displays LUMO density on the pyridinium motif,
provided the product, albeit in low yield (12%).
Scheme 1. Emerging Strategies for Radical Formation
Inspection of the corresponding reaction mixtures by GC−
MS suggested that the formation of fluorobenzylated pyridine
byproducts was a major contributor to the mass balance. Thus,
we speculated that fluorobenzyl radical formed under reaction
conditions and either attacked the pyridinium salt (1d) or the
resulting pyridine in a Minisci-type reaction.49,50 Indeed, when
the 4-position was blocked (1e and 1f), we observed a slightly
improved albeit still meager yield. 1g resulted in the formation of
a colored electron donor−acceptor complex that was consumed
but did not result in product formation. We next explored both
collidinium (1h) and Katritzky51 (1i) salts, whose susceptible
positions were blocked. In both cases, the Minisci product could
not be detected, and the yield nearly doubled. A direct
comparison with the corresponding benzyl bromide revealed
the enhanced reactivity of the pyridinium-derived salts,
suggesting that electron capture could be enhanced by
substitution.
Encouraged by the positive results of our initial exploration
and those of Glorius,52−54 Lautens,53 and Aggarwal,55 who used
Katritzky salts in deaminative couplings of primary amines via
photoredox catalysis, and related work56,57 that provided strong
precedent, we set out to optimize the reaction conditions (Table
1). While both the trimethyl- (1h) and triphenylpyridinium (1i)
Table 1. Optimization Table
reaction41−44 using benzyl bromide-derived salts and conditions
that have been used for reductive coupling in our lab45−48
(Scheme 2). We found that quaternary ammonium, imidazo-
lium, and phosphonium salts showed no reactivity under these
conditions. The molecular orbitals obtained using semiempirical
̈
Huckel calculations demonstrate that the LUMO lies primarily
on the fluorobenzene fragment rather than on the added
nucleophilic component, which explains the lack of reactivity
c
Scheme 2. Search for Redox-Active Salts
a
Conversions and product ratios were determined by 19F NMR
spectroscopy.
salts resulted in higher yields compared with less substituted
versions, a closer inspection of the 19F NMR spectra of the
reaction mixtures revealed that trimethylpyridinium 1h
produced far fewer side products (see the SI). Given this and
the fact that triphenylpyridinium 1i is derived from the
corresponding expensive oxopyrylium salt ($2376/mol) rather
a
b
The reaction went to completion within 8 h. The reaction did not
c
go to completion and reached 79% conversion after 72 h. Conversion
was determined by 19F NMR spectroscopy.
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Letter
d
than inexpensive collidine ($29/mol), we elected to continue
optimization using collidinium salt 1h.
Scheme 3. Scope Studies
With reductive conditions, which included catalytic Ir(ppy)3,
DIPEA, and blue light, we observed complete conversion within
6 h, but the desired product was a minor product (23%) (Table
1, entry 1). While minor amounts of radical termination
products were identified (3′ and 3″), we were encouraged to see
that the majority of the mass balance appeared to be derived
from a benzyl radical that had formed the desired C−C bond
and could, if nudged in the right mechanistic direction, lead to
product. More specifically, it appeared that rather than
terminating to give the desired product, it underwent one or
two propagation steps to give products 3a′ and 3a″. Dilution of
the reaction mixture (entry 2) helped somewhat, giving a
correspondingly higher yield, but slowed the reaction. Together
these experiments suggested that controlling the rate of
termination would be vital to achieving product selectivity.
We postulated that identification of the appropriate catalyst
could facilitate reduction of the intermediate radical.58,59
Indeed, a photocatalyst screen (see the SI) showed that while
the iridium catalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 gave more
sluggish conversion (entry 3), the critical ratio of desired to
undesired products improved by an order of magnitude.
Furthermore, increasing or decreasing the photocatalyst loading
increased (entry 5) or decreased the product ratio (entry 6),
respectively.
Changing the catalyst to Ru(bpy)3 (Table 1, entry 4), which
has a similar reduction potential (E1/2(II/I) = −1.33 V vs SCE),1
gave very sluggish conversion and no detectable product
formation, suggesting that the photocatalyst plays a nuanced
role in the reaction. Attempts to use NBu3 (entry 8) instead of
DIPEA (entry 3) led to slightly faster conversion but gave
substantial amounts of a compound derived from combination
of the amine and nitrile.60,61 Speculating that the off-cycle use of
the amine retarded the reaction at higher conversions, we
investigated the use of more amine (entry 3 vs entries 9 and 10).
Indeed, moving from 2 to 4 equiv increased the conversion from
50% to 100% and decreased the reaction time from 46 to 16 h.
Importantly, as the desired reaction was able to take place
throughout the entirety of the reaction period, the product
distribution shifted in favor of the desired product. With
evidence suggesting the involvement of the photocatalyst in the
termination step, we investigated the effect of water on the
reaction (entries 11 and 12). Indeed, the inclusion of 10 equiv of
H2O further enhanced the product distribution to 29.3:1 and
accelerated the reaction (12 h), resulting in an 88% yield.
Finally, individual control studies evidenced the critical aspect of
each reaction component (entry 13).
a
b
The 4-methylpyridinium salt was used. The catalyst loading was 0.5
c
d
mol %. 19F NMR yield. Yields are of isolated products, unless
otherwise noted.
secondary benzylic substrate (3l) also gave a good yield,
highlighting the ability to rapidly and significantly modify the
carbon framework of the substrate. The mild reaction conditions
are compatible with a wide range of functional groups, such as
nitrile (3f), ester (3d), ether (3j), and bromide (3b and 3c).
Importantly, all of these substrates were engaged photocatalyti-
cally using the same conditionsa feat that would have been
challenging using the corresponding halides. The collidinium
salts offer protection to otherwise-sensitive heterocycles such as
thiophene62 (3m) and naphthalene63 (3h), which might be
expected to undergo radical addition. We expect the broad
functional group tolerance to facilitate further synthetic
elaboration. Other electron-deficient alkenes worked well in
the reaction (3n−s), with the ester substituent of acrylates
exhibiting minimal influence (3n and 3o) while methacrylate
(3p) was slightly more prone to propagation. Similarly,
cinnamate (3s) gave the product in modest yield. Cyclic enones
proved to be competent (3q, and 3r), giving the fluorobenzy-
lated products in good yields. Other alkenes also proved to be
competent (see the SI). Interestingly, the use of α-methylstyrene
resulted in the formation of product (3t) and higher-order
oligiomers. The scope suggests that different reaction
mechanisms may be operative depending on the alkene. The
use of the bench-stable crystalline collidinium salts also
facilitates workup of the reaction. Simple extraction followed
by acidic washes removes any excess DIPEA, collidine
byproduct, and (if present) any unreacted collidinium salts.
This is in stark contrast to the Katritzky salt, which produces
triphenylpyridine, which must be removed chromatographically.
Likewise, if the benzyl halide were used, any excess would also be
expected to require removal from the organic extracts.
Having identified the optimal conditions (Table 1, entry 12),
we examined the scope of collidinium salts with acrylonitrile
(Scheme 3). A broader range of collidinium salts was prepared
(see the SI). The reaction worked well for benzylic collidinium
salts with electron-withdrawing groups (3a, 3d, and 3f),
electron-neutral groups (3b, 3c, and 3g), and electron-donating
groups (3i and 3j), which would have been a challenging feat for
the corresponding halides. This strategy could be extended to
sterically demanding, ortho-flanked benzylic substrates (3e and
3k) by use of the 4-methylpyridine-derived salts. Apparently, the
bulk of the benzyl component, which made nucleophilic
substitution more challenging, also served to protect these
salts from undergoing the Minisci-type benzylation that we had
observed earlier with less sterically demanding benzylpyridi-
nium salts. Furthermore, the 4-methylpyridinium salt of a
Our working mechanism of the reaction is shown in Scheme
4. The reaction begins with absorption of a blue photon to give
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a
reduction of the radical to carbanion IV (estimated reduction
potential ≈ −0.9 to −1.1 V vs SCE).76,77 The photocatalyst
concentration is expected to influence the lifetime of III, which
may also undergo oligimerization; therefore, it is expected to
impact product distribution, which we observed.
Scheme 4. Working Mechanism
Returning to our initial goal of dual catalysis, in a preliminary
catalytic experiment with 2-(chloromethyl)-1,3,5-trimethylben-
zene (Scheme 6), we observed that a 20 mol % loading of 4-
Scheme 6. Preliminary Attempt to Achieve Catalytic
Activation
a
b
Assay yield determined by GC−MS. Without 4-methylpyridine, the
conversion was 38% after 26 h.
a
(A) Our current understanding of the mechanism. (B) Literature
redox values of lr[dF(CF3)ppy]2(dtbbpy)pF6. (C) Fluorescence
quenching experiments on Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1.25 μM)
using collidinium salt ([1h] = 25 mM) and amine ([DIPEA] = 25
mM). All spectra were recorded in MeCN in a 1 cm path length
quartz cuvette at 25 °C.
methylpyridine is capable of achieving catalytic turnover and
significantly enhancing the rate of benzylation. While some
background reaction was observed, it was substantially slower
(38% vs 100% conversion; see the SI for more details). This
result supports the validity of the underlying concept and
provides an initial point for further investigation of nucleophiles
that can strike the appropriate balance of nucleophilicity and
reducibility to allow the catalytic transformation of non-redox-
active electrophiles.
In conclusion, we have demonstrated that the use of
commercially available collidinium salts is a viable strategy
that enables photoredox catalysis to mildly and efficiently engage
previously sluggish and unreactive alkyl halides. While this study
focused on the stoichiometric work, we have shown that dual
catalysis is feasible and that further development is warranted.
Pragmatically, collidinium salts are easy-to-make, easy-to-
handle, photochemically stable, and bench-stable crystalline
salts that are redox-active alternatives to halides. Furthermore,
all of the reaction components are water-soluble, which
facilitates product isolation and potentially allows their use in
complex settings.
strongly oxidizing Ir(III)* [Ir*(III)/Ir(II) = 1.21 V vs SCE in
CH3CN],64 followed by reductive quenching by the amine65,66
(NR3 ≈ 0.50 V vs SCE).67,68 This is supported by Stern−Volmer
analysis (5a). Next, the reduced Ir(II) undergoes SET to
collidinium salt 1h69,70 (Ir(II/III) = −1.37 V vs SCE;64
estimated E1/2 = −1.27 V vs SCE in DMF),71 giving collidinium
radical I and completing cycle A. Subsequently, I undergoes
unimolecular fragmentation72 to give collidine and benzylic
radical II. Addition of II to acrylonitrile generates radical
intermediate III. Hydrogen atom transfer (HAT) from the
amine radical cation yields the product (path a).
However, several observations called this explanation into
question, namely, the effect of the photocatalyst loading on the
product distribution (Table 1, entries 1, 5 and 6) and the
enhanced rate and selectivity upon addition of water (Table 1,
entry 12). Indeed, we observed a solvent kinetic isotope effect of
kH/kD = 2.0 when we used 10 equiv of D2O (Scheme 5).
ASSOCIATED CONTENT
* Supporting Information
■
sı
Scheme 5. Isotope Experiments
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00173.
FAIR data, including the primary NMR FID files, for
compounds 1a, 1e−t, and 3a−t (ZIP)
Procedures, spectra, and additional experiments (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Furthermore, the deuterium incorporation experiment (Scheme
5) revealed that the use of D2O resulted in only partial
incorporation of the deuterium (30%) in the α-position of the
nitrile product. On the basis of the O−H bond strength of water
(118.8 kcal/mol)73 and the Cα−H bond strength of the product
(89.0 kcal/mol),74 HAT from water is improbable. However,
protium incorporation (70%) in the presence of D2O suggests
that HAT (path a) indeed occurs, with the likely donor being
DIPEA radical cation.3,75 The observed rate enhancement of the
desired reaction upon inclusion of water may be due to proton-
coupled electron transfer (PCET) (path B) that facilitates
Jimmie D. Weaver, III − Department of Chemistry, Oklahoma
State University, Stillwater, Oklahoma 74078, United States;
orcid.org/0000-0003-4427-2799;
Email: Jimmie.Weaver@okstate.edu
Author
Manjula D. Rathnayake − Department of Chemistry,
Oklahoma State University, Stillwater, Oklahoma 74078,
United States
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̈
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Complete contact information is available at:
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Notes
The authors declare the following competing financial
interest(s): The authors have licensed collidinium salt
technology to Weaver Labs, LLC, of which J.D.W. has
ownership.
ACKNOWLEDGMENTS
■
We thank the NSF (CHE-1453891).
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