Catalyst-Free Decarbonylative Trifluoromethylthiolation Enabled by Electron Donor-Acceptor Complex Photoactivation

Article abstract of DOI:10.1002/adsc.202100469

A catalyst- and additive-free decarbonylative trifluoromethylthiolation of aldehyde feedstocks has been developed. This operationally simple, scalable, and open-to-air transformation is driven by the selective photoexcitation of electron donor-acceptor (EDA) complexes, stemming from the association of 1,4-dihydropyridines (donor) with N-(trifluoromethylthio)phthalimide (acceptor), to trigger intermolecular single-electron transfer events under ambient- and visible light-promoted conditions. Extension to other electron acceptors enables the synthesis of thiocyanates and thioesters, as well as the difunctionalization of [1.1.1]propellane. The mechanistic intricacies of this photochemical paradigm are elucidated through a combination of experimental efforts and high-level quantum mechanical calculations [dispersion-corrected (U)DFT, DLPNO-CCSD(T), and TD-DFT]. This comprehensive study highlights the necessity for EDA complexation for efficient alkyl radical generation. Computation of subsequent ground state pathways reveals that S_H2 addition of the alkyl radical to the intermediate radical EDA complex is extremely exergonic and results in a charge transfer event from the dihydropyridine donor to the N-(trifluoromethylthio)phthalimide acceptor of the EDA complex. Experimental and computational results further suggest that product formation also occurs via S_H2 reaction of alkyl radicals with 1,2-bis(trifluoromethyl)disulfane, generated in-situ through combination of thiyl radicals. (Figure presented.).

Full text of DOI:10.1002/adsc.202100469

Title: Catalyst-Free Decarbonylative Trifluoromethylthiolation Enabled
by Electron Donor–Acceptor Complex Photoactivation
Authors: Alexander Lipp, Shorouk Badir, Ryan Dykstra, Osvaldo
Gutierrez, and Gary Molander
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202100469
Link to VoR: https://doi.org/10.1002/adsc.202100469

10.1002/adsc.202100469
Advanced Synthesis & Catalysis
Very Important Publication
FULL PAPER
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
Catalyst-Free Decarbonylative Trifluoromethylthiolation
Enabled by Electron Donor–Acceptor Complex Photoactivation
Alexander Lipp,a,‡ Shorouk O. Badir,a,‡ Ryan Dykstra,b,‡ Osvaldo Gutierrez,b,* and
Gary A. Molandera,*
a
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street,
Philadelphia, Pennsylvania 19104-6323, United States. Contact: +1 (215) 573-8604, gmolandr@sas.upenn.edu
[for corresponding author(s) please include phone and fax number(s) and e-mail address(es)]
Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742, United States.
b
Contact: +1 301-405-8388, ogs@umd.edu
These authors contributed equally.
‡
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. A catalyst- and additive-free decarbonylative This comprehensive study highlights the necessity for EDA
trifluoromethylthiolation of aldehyde feedstocks has been complexation for efficient alkyl radical generation.
developed. This operationally simple, scalable, and open-to- Computation of subsequent ground state pathways reveals
air transformation is driven by the selective photoexcitation that SH2 addition of the alkyl radical to the intermediate
of electron donor–acceptor (EDA) complexes, stemming radical EDA complex is extremely exergonic and results in
from the association of 1,4-dihydropyridines (donor) with N- a charge transfer event from the dihydropyridine donor to
(trifluoromethylthio)phthalimide (acceptor), to trigger the N-(trifluoromethylthio)phthalimide acceptor of the EDA
intermolecular single-electron transfer events under ambient- complex. Experimental and computational results further
and visible light-promoted conditions. Extension to other suggest that product formation also occurs via SH2 reaction
electron acceptors enables the synthesis of thiocyanates and of alkyl radicals with 1,2-bis(trifluoromethyl)disulfane,
thioesters, as well as the difunctionalization of generated in-situ through combination of thiyl radicals.
[1.1.1]propellane. The mechanistic intricacies of this
photochemical paradigm are elucidated through
a
Keywords: aldehydes, density functional calculations;
electron donor-acceptor complexes; photocatalysis; radical
reactions; trifluoromethylthiolation
combination of experimental efforts and high-level quantum
mechanical calculations [dispersion-corrected (U)DFT,
DLPNO-CCSD(T), and TD-DFT].
feedstocks has gained considerable momentum.[4,5]
Owing to their widespread availability, aldehydes are
attractive commodity chemicals that have been
Introduction
Fluorinated functional groups have long captured the
attention of the synthetic community because of the
distinct characteristics that they impart onto bioactive
subunits. Fluorine incorporation has direct effects on
a molecule’s chemical, physical, and biological
properties, such as its pKa, dipole moment, and
molecular conformation.[1] These effects, in
combination, have enormous implications in their
applications to the pharmaceutical industry, where the
optimization of pharmacokinetics as well as
adsorption, distribution, metabolism, and excretion
(ADME) properties have witnessed a renaissance
following the rise of fluorinated small molecules.[2]
As a consequence of these factors, fluorinated motifs
are embedded in more than 25% of commercialized
drug products.[3] As an important representative, the
trifluoromethylthio ether (–SCF3) group is known to
exhibit high electronegativity and lipophilicity
(Hansch parameter R = 1.43), leading to enhanced
metabolic stability and transmembrane permeability
in drug candidates (Scheme 1A).[4] In this vein, the
harnessed
in
deoxygenative
and
-C–H
trifluoromethylthiolation.[6] Recently, photoredox-
mediated hydrogen atom transfer (HAT) catalysis has
been utilized to generate acyl radicals from aldehydes
to access trifluoromethylthio esters (Scheme 1B).[7] In
this context, the use of aldehydes as selective alkyl
radical precursors for the decarbonylative
construction of C(sp3)–SCF3 bonds would represent a
complementary strategy. In particular, the
development of selective trifluoromethylthiolation
processes for late-stage functionalization of complex
targets under redox-neutral and additive-free
conditions is of great significance in medicinal
chemistry.
Recently, visible-light photocatalysis has been
enlisted to facilitate the construction of challenging
structural motifs with high functional group
tolerance.[8] Through single electron transfer (SET)
paradigms, a photoexcitable catalyst undergoes
oxidative or reductive quenching pathways to yield
reactive carbon- or heteroatom-based radicals that
engage in subsequent synthetic operations. However,
the majority of these processes rely on the redox
development
of
synthetic
strategies
for
diverse
trifluoromethylthiolation
employing
1
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10.1002/adsc.202100469
Advanced Synthesis & Catalysis
potentials of expensive transition-metal complexes,
largely based on ruthenium and iridium. These
manifolds are further complicated by the
oxidation/reduction steps of the photocatalyst.
In previous synthetic studies, we demonstrated that
1,4-dihydropyridines (DHPs) undergo oxidative,
homolytic fragmentation under classical photoredox
conditions.[10] DHPs are readily accessible from
commercially available aldehydes in one step and are
known to engage in radical-mediated alkylation.[10]
Specifically, DHPs function as masked aldehydes to
deliver alkyl radicals selectively, circumventing the
formation of undesired, acylated byproducts as well
as the need for elevated temperatures required for
efficient CO extrusion in decarbonylative pathways
(Scheme 1C).[11] Recent methods based on
photochemical and persulfate-mediated oxidation of
DHPs to enable carbon–carbon bond-forming
processes illustrate the potential of these building
blocks to undergo functionalization through strategies
that are unavailable to the parent aldehydes.[10,11a]
Inspired by these efforts, we envisioned the use of
DHPs in conjunction with electron-deficient N-
(trifluoromethylthio)phthalimide[12] to form electron
donor–acceptor complexes that facilitate the
generation of open-shell reactive species in the
absence of precious transition-metal-based complexes.
Herein, we harness the synthetic utility of EDA
photochemistry to enable a catalyst- and additive-free
decarbonylative trifluoromethylthiolation of aldehyde
feedstocks under open-air and ambient reaction
conditions (Scheme 1D). In recognition of the
growing utility of organic reactions promoted by
EDA complex photoactivation,[9] this transformation
also serves as a case study whereby quantum
mechanical calculations are used to investigate the
mechanism, electronic properties, and dynamics to
gain a deeper understanding of the underlaying
charge transfer processes.
Scheme 1. Envisioned decarbonylative trifluoromethyl-
thiolation of aldehyde feedstocks; PC = photoredox
catalyst.
An alternative approach circumventing the need
for exogenous photoredox catalysts exploits the
association of electron-donor/electron-acceptor pairs
to form new molecular aggregates in the ground state,
exhibiting red-shifted absorption bands.[9] Typically,
the energy of this transition lies within the visible
light region. Direct photoexcitation of such electron
donor–acceptor (EDA) complexes induces an
intermolecular single electron transfer (SET) event,
generating a radical ion pair. An inherent challenge in
EDA photochemistry stems from competitive back
electron transfer (BET) events that restore the ground
state of the complex. To overcome this complication
and facilitate the otherwise improbable cage escape,
the acceptor typically carries a suitable leaving group,
enabling elimination of excess charge by rapid bond
scission.[9] The photoactivation of EDA complexes
has allowed the introduction of new synthetic
frameworks to tackle major synthetic challenges not
addressed in conventional photoinduced pathways
(high redox potentials, oxygen- and water-sensitivity,
site-selectivity in oxidation- and reduction-labile
systems, etc.).[9] However, although experimental
evidence for the intermediacy of radical species in
EDA photochemistry is strong, the mechanism and
molecular-level understanding of these processes
remain largely underexplored.
Results and Discussion
From the outset of our investigation, we recognized
the key role of solvent in the proposed
trifluoromethylthiolation, as in this type of charge
transfer-catalyzed processes the solvent cage heavily
affects the molecular assembly and formation of EDA
complexes.[13] Under the optimized reaction
conditions, experiments were carried under blue
Kessil irradiation (λmax = 456 nm) in acetone as the
optimal solvent (see the Supporting Information). No
product formation was detected in the absence of
light, validating the photochemical nature of this
transformation. In contrast to radical-mediated
alkylation catalyzed by an external photocatalyst, this
EDA paradigm circumvents side reactions in the
presence of oxygen that would result from triplet
energy transfer.
We next examined the scope of this transformation
using DHPs featuring diverse alkyl substituents at the
C4-position (Scheme 2; left). Both cyclic and acyclic
derivatives
delivered
the
desired
trifluoromethylthiolated products in excellent yields.
Of note, alkene (3g, 3i) and halide (3c, 3o, and 3p)
functional handles are accommodated, providing
2
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10.1002/adsc.202100469
Advanced Synthesis & Catalysis
linchpins that have the potential to drive molecular
complexity. The scope was further extended to
stabilized primary and secondary -oxy systems. In
particular, carbohydrate-derived DHPs exhibiting a
wide range of protecting groups routinely utilized in
use of structurally related 4-acyl-1,4-DHPs[15]
provided
access
to
the
corresponding
similar
trifluoromethylthio
esters
under
a
photochemical paradigm (Scheme 2; right). In
general, both electron-donating and electron-
glycodiversification efforts are well tolerated (3q–3v). withdrawing substitution patterns are amenable. The
Notably, the installation of the 2,4-dichlorophenoxy
group (3p), a key motif in herbicides,[14] proved
successful. Unstabilized primary- and aryl radicals
cannot be generated from the corresponding DHPs
because of competitive C–H bond scission.[10] The
introduction of heteroaryl (5g) as well as aliphatic
(5l) frameworks was equally fruitful. Notably, in the
case of 5l, competitive C(sp3)–SCF3 bond formation
stemming from decarbonylation of the intermediate
aliphatic acyl radical was not observed.
Scheme 2. Scope of the developed trifluoromethylthiolation. Reaction conditions: N-(trifluoromethylthio)phthalimide (2,
0.5 mmol, 1.0 equiv), alkyl- (1a–v, blue, 24 h reaction time) or acyl-DHP (4a–l, red, 4 h reaction time) (each 1.0 mmol,
2.0 equiv) in acetone (2.5 mL, 0.2 M) under blue light irradiation (Kessil lamp, λmax = 456 nm). Yields correspond to
1
isolated products after chromatographic purification. aProduct volatile, yield was determined via H NMR with 5-
bromopyrimidine (0.25 mmol) as internal standard (IS). See the Supporting Information for further details.
Industry’s dependence on photochemical processes
highlights the necessity for operationally simple,
inexpensive, and scalable strategies for the
incorporation of medicinally relevant motifs from
abundant feedstocks.[16] To assess the scalability of
the developed method, glycosidic derivative 3r was
synthesized on gram scale using a reduced loading of
the DHP precursor 1r (1.2 equiv) without
compromising the yield (Scheme 3A). To
demonstrate the versatility of this EDA platform, the
use of N-(thiocyano)phthalimide (6) as the electron
acceptor was explored to grant access to the
corresponding thiocyanates, a class of valuable
synthetic intermediates present in natural products
and biologically active molecules (Scheme 3B).[17]
The applicability of this method was further
expanded to N-(phenylthio)phthalimide (7) to
generate thioesters.
Driven by the robust reactivity of DHPs and the
ever-increasing necessity for novel therapeutics, we
examined the feasibility of a three-component EDA
paradigm to construct trifluoromethylthiolated
bicyclo[1.1.1]pentane (BCP) products through
reaction with [1.1.1]propellane (Scheme 3C).[9e]
These BCP derivatives serve as bioisosteres for
arenes, internal alkynes, and tert-butyl groups in
medicinal settings.[18] Employing strain-release as a
driving force (~60 kcal/mol),[19] conjunctive 1,3-
difunctionalization of propellane was accomplished
under the optimized reaction conditions (Scheme 3C;
10i, 10r). This strategy allows the construction of
sequential chemical bonds from commodity
chemicals in one pot to access complex structural
3
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10.1002/adsc.202100469
Advanced Synthesis & Catalysis
motifs rapidly, representing a rare example of EDA-
based multicomponent photochemistry.[9]
Figure 1. UV/vis absorption spectra of N-
(trifluoromethylthio)phthalimide (2, 0.2 M, 1.0 equiv, red
band), DHPs 1a or 4a (0.4 M, 2.0 equiv, green band), and
mixtures thereof (blue band) in acetone.
Scheme 3. Gram scale experiment, extension to other
electron acceptors, and multicomponent reaction.
To probe the formation of charge-transfer
complexes, UV/vis absorption studies were
Figure 2. Job plot for a mixture of N-(trifluoromethylthio)-
phthalimide (2) and DHP 1a in acetone (0. 4 M).
performed.
Although
a
solution
of
N-
(trifluoromethylthio)-phthalimide (2) in acetone (0.2
M, reflecting the actual reaction concentration)
displays no absorbance in the visible light region, a
Once we established the viability of DHPs as
alkylating agents in charge-transfer processes, we
investigated the influence of the 1,4-dihydropyridine
backbone on the outcome of the developed
trifluoromethylthiolation (Scheme 4A). At the outset,
reaction with N-methyl-DHP 11 did not result in
product formation, highlighting the importance of the
N-H motif for reaction efficiency. We speculate that
proton transfer from the N-H group to the developing
phthalimide anion facilitates the generation of the
neutral species (phthalimide and pyridine).
Further, cyano substitution at the C3 and C5
positions (12) led to trace product formation, which
was rationalized by competitive C–H bond scission
yielding 4-alkylpyridine derivatives selectively. With
respect to the ester substitution pattern, no significant
impact on the reactivity was detected (note that the
slightly reduced yield for methyl ester derivative 13
results from limited solubility in acetone, see the
Supporting Information). This is in contrast to
previously reported C–H alkylation protocols in
which a correlation between the steric bulk of the
ester substituents at C3 and C5 and the reactivity of
the corresponding DHPs was observed in the
presence of persulfate as a terminal oxidant (Scheme
mixture with 4-alkyl-1,4-DHP 1a exhibits
a
significant bathochromic shift (Figure 1A). Upon
mixing, a yellow color appears, accompanied by an
absorption band tailing into the wavelength region of
blue Kessil irradiation. A Job plot revealed a 1:1
stoichiometry of the corresponding EDA complex
(Figure 2). Further studies using the Benesi-
Hildebrand[20] method revealed an association
constant (kEDA) of 0.6 M–1 of DHP and N-
(trifluoromethylthio)phthalimide (see the Supporting
Information).
Furthermore, the intermediacy of alkyl radicals
was validated through TEMPO trapping experiments
(see the Supporting Information). In the case of 4-
acyl-1,4-DHP 4a, no bathochromic shift was detected,
suggesting a plausible mechanistic scenario involving
direct photoexcitation of these species (vide infra) to
generate acyl radicals via homolytic fragmentation
(Figure 1B).[15]
4
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10.1002/adsc.202100469
Advanced Synthesis & Catalysis
4B).[11a] The enhanced reaction efficiency was
attributed to increased steric hindrance at the C4-
position of the pyridine byproduct generated upon
homolytic fragmentation. This could limit
competitive rebound of the alkyl radical, which,
followed by an oxidative rearomatization event,
yields the corresponding Minisci byproduct (vide
infra). In the developed catalyst-free EDA paradigm,
this detrimental side reaction is circumvented because
of the absence of a terminal oxidant.
Figure 3. Validation of disulfide 16 as reaction
intermediate in one potential pathway to product formation
(see the Supporting Information for details).
The
computational
performed
studies
using
began
with
optimizations
unrestricted
dispersion-corrected DFT calculations (UB3LYP-D3)
with Ahlrich and coworkers’ def2-SVP basis set in
implicit DMSO solvent using the conductor-like
polarizable continuum model (CPCM).[22] Energetics
were refined by performing single point calculations
using def2-TZVPP basis set with the B3LYP-D3
method and implicit solvent. In addition, open shell
Domain-based Local Pair and Natural Orbital
Couple-Cluster calculations with single-, double-, and
perturbative triple excitations [DLPNO-CCSD(T)]
single point calculations were performed using the
def2-TZVPP basis set to account for dynamic
correlation.[23] This method has been benchmarked
and shown to give a mean absolute deviation of ~0.3
kcal/mol for both the Friedrich and Hänchen and S66
sets using the Normal-PNO threshold that were used
here.[24] As continuum solvation models are not
available for DLPNO-CCSD(T) calculations,
solvation corrections were obtained from the
Scheme 4. Influence of the DHP backbone.
Finally, monitoring the reaction progress via 19F
NMR analysis revealed the intermediacy of
disulfide 16 [S2(CF3)2]
(Figure
3)
in
the
trifluoromethylthiolation of both 4-alkyl- and 4-acyl-
1,4-DHPs (see the Supporting Information). In
separate experiments, this intermediate was prepared
independently and subsequently converted to product
in the presence of excess 1a or 4a (Figure 3). In these
cases, alkyl- or acyl radicals were presumably
generated through homolytic cleavage of the
corresponding photoexcited DHPs (vide infra).[15,21]
For 4-acyl-DHPs, this fragmentation occurs rapidly,
reflecting their high absorption coefficients in the
blue wavelength region. In contrast, without N-
(trifluoromethylthio)phthalimide (2) as electron
acceptor, the fragmentation of 4-alkyl-DHPs is slow
under blue Kessil irradiation (only ~5% of 1a
fragments upon irradiation of a 0.4 M solution of this
DHP in acetone using the standard setup, 24 h).
Although sufficient to validate the intermediacy of
disulfide 16 (Figure 3), it is evident that in the
presence of 2 as an acceptor species, the major
pathway for alkyl radical formation is photoexcitation
of the corresponding EDA complex followed by a
charge-transfer event (see the computational
investigation).
UB3LYP-D3/def2-TZVPP-CPCM
single
point
calculations to correct the energetics. Time-
dependent density functional theory (TD-DFT)
calculations at the B3LYP-D3/def2-SVP-CPCM level
were used to study the excited state pathways. To see
how it would influence the energetics of key
pathways, single point calculations were run using
both DFT and TDDFT with acetone set as the
implicit solvent, which gave almost identical
energetics as obtained using DMSO (see the
Supporting Information). 3D structures of molecules
were generated using CYLview,[25] while molecular
orbitals and electronic density difference maps were
visualized using GaussView 5. For simplicity, the
discussion in the main manuscript is largely limited
to the alkyl-DHP systems for which a bathochromic
shift was observed experimentally (Figure 3). For
acyl counterparts, a brief summary of key findings is
presented here, and the full details are provided in the
Supporting Information.
To begin the mechanistic studies, the
thermodynamics of the potential competing
photochemical pathways that could lead to the
5
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10.1002/adsc.202100469
Advanced Synthesis & Catalysis
formation of the putative alkyl radical intermediate
were explored (Scheme 5). In particular, alkyl radical
formation as a result of direct excitation of the
dihydropyridine scaffold A1 followed by single
electron transfer (SET) with phthalimide B1 (Path A;
red)[26] or direct homolytic cleavage (Path B; green)
was envisioned. Alternatively, dihydropyridine A1
and phthalimide B1 could first associate to form
electron donor-acceptor (EDA) complex C1 then
undergo excitation to generate the alkyl radical with
concomitant formation of radical EDA complex D2’
(Path C; blue).[27]
that goes out to ~466 nm (see the Supporting
Information for computed UV/vis spectra). On the
other hand, EDA complex C1 shows the lowest lying
singlet excited state where the significant absorbance
is S2, with max ~354 nm, and a tail extending to ~495
nm. These results suggest that EDA complexation
should result in bathochromic shifting as observed
experimentally (Figure 1A). Also in agreement with
experiment, DHP alone shows very little absorbance
at 450 nm, highlighting the crucial role of EDA
complexation for efficient formation of alkyl radicals.
Even though scenarios A, B, and C are all
thermodynamically feasible (Scheme 5), excitation of
EDA complex C1 is the major pathway for alkyl
radical generation.
Closer inspection of the molecular orbitals (MOs)
corresponding to the strongest electronic transitions
of DHP A1 and EDA complex C1 (Scheme 6) reveals
complete charge transfer from the DHP to the
phthalimide core via internal conversion from excited
states C1-S2 to C1-S1 that allows the formation of a
more stable intermediate C1-S1’, which then
undergoes C–C bond cleavage, liberating the alkyl
radical. In particular, both singlet excited states
responsible for absorbance, A1-S1 and C1-S2, (see the
Supporting Information for details) have maximum
absorption at wavelengths corresponding to ~83 and
~81 kcal/mol, respectively. In contrast, the lowest
lying singlet excited state for the EDA complex, C1-
S1, is found to have a lambda max much lower in
energy (~54 kcal/mol). Moreover, the singlet
excitation of the DHP (A1-S1) could be described as
primarily a transition from the HOMO containing the
C–C σ-bond between the isopropyl group and the
DHP scaffold to the π* LUMO on the DHP. The
second singlet excited state of the EDA complex C1-
S2 is of a similar nature to A1-S1 with the only
difference being the inclusion of the π* orbitals on
the phthalimide moiety. Overall, as both excitations
are transitions centered about the dihydropyridine,
little to no difference in energy is observed between
them. On the other hand, excitation C1-S1 is a
transition from the HOMO on the DHP to the π*
LUMO on the phthalimide, ascribed to a charge
transfer event.
Scheme 5. Energetics of competing light-promoted alkyl
radical formation (free energies [DLPNO-CCSD(T)/def2-
TZVPP//UB3LYP-D3/def2-SVP-CPCM(DMSO)]
kcal/mol).
in
We found that direct excitation of A1 followed by
SET (Path A; red) is uphill in energy by 57.7
kcal/mol, while alkyl radical formation via homolytic
C–C bond cleavage (Path B; green) is
thermodynamically more favorable by ~9 kcal/mol.
On the other hand, EDA complexation to form C1 is
nearly isoenergetic to the separated species. In turn,
photoexcitation of C1 could lead to alkyl radical and
intermediate D2’ (Path C; blue) which is found
slightly uphill in comparison to Path B (by ~2
kcal/mol). Overall, these results suggest that alkyl
radical formation from either direct photoexcitation
of A1 or EDA complex C1 (Path B and C,
respectively) are both energetically feasible, while
alkyl radical formation via SET (Path A; red) is less
likely due to the formation of unstable charge-
separated species.
The similarities between A1-S1 and C1-S2 and the
differences of C1-S1 are further emphasized by the
electron density difference maps (EDDMs) illustrated
in Scheme 6B. EDDMs are used to show the change
in electron density of the excitation of interest with
respect to the ground state electron density. Red
indicates a decrease in electron density while blue
indicates an increase in electron density. As can be
seen from the EDDMs of A1-S1 and C1-S2, electron
density is reduced form the isopropyl moiety and the
nitrogen in the DHP ring, while electron density
increases about the methyl groups and the esters on
the DHP. An increase in electron density is found to
occur on the aryl portion of the phthalimide C1-S2,
which is expected when compared to the major
electronic transition of this excited state. On the other
hand, excited state C1-S1 shows complete electron
Next, we turned to TD-DFT calculations to
investigate the energetic feasibility of the electronic
transitions leading to alkyl radical formation (Scheme
6).[28] Consistent with experiment, computations show
that the excitation of DHP A1 has its lowest lying
singlet excited state S1 with max ~344 nm and a tail
6
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10.1002/adsc.202100469
Advanced Synthesis & Catalysis
density depletion from the DHP moiety, and similarly
an increase in electron density occurs about the entire
π system of the phthalimide. Furthermore, as shown
in Scheme 6A, optimization of the S1 excited state of
the DHP leads to A1-S1’, and is associated with
substantial elongation of the C–C σ-bond between the
alkyl moiety and the DHP core (from 1.57 to 1.70 Å).
Subsequent C–C bond cleavage can then lead to the
formation of the corresponding isopropyl radical A2
(see the Supporting Information for full pathway). On
the other hand, optimization of C1-S1, from rapid
internal conversion of C1-S2, leads to C1-S1’ with
significant bond elongation between the alkyl and
DHP moieties. Interestingly, no elongation of the N–
S σ-bond was observed upon optimization of
excitation C1-S1, suggesting that SCF3 radical
dissociation is less likely to occur upon relaxation of
the lowest lying excited state.
Scheme 6. Excited state potential energy surfaces of paths B and C and visualization of lowest-lying excitations. (A) Free
energies of excited state molecules computed using TD-DFT, relative to free energy of ground state molecules computed
using DFT [B3LYP-D3/def2-SVP-CPCM(DMSO)] in kcal/mol. Wavelengths of excitations computed relative to ground
state electronic structure using total energy. Bond distances are labeled in Å ngstroms (Å ). (B) Molecular orbitals of the
largest contributing transitions (Transitions) and electron density difference maps (EDDMs) of lowest lying singlet excited
states as indicated. Isovalues for molecular orbitals and EDDMs are 0.02 and 0.0004 e-/au3, respectively.
Following our computational investigation of
photoexcitation and formation of alkyl radicals, we
next explored the thermodynamic feasibility of three
potential pathways to product formation.
kcal/mol). In turn, reorganization of the π-stacked
complex F1 to the hydrogen bonded complex G1 is
energetically favorable by 5.6 kcal/mol. Finally,
proton transfer via tautomeric transition state G1-TS-
H1 allows dissociation of the pyridine and
phthalimide molecules.
(1) As shown in Scheme 7, from the dissociated
isopropyl radical and the corresponding radical EDA
complex D2 (Path C, Complex Pathway), product
can be formed via SH2 addition of the isopropyl
radical to the SCF3 moiety bound to the phthalimide
core (D2-TS-E1). Despite numerous attempts, we
were not able to locate transition state D2-TS-E1.
However, scans of this potential energy surface
revealed the process to be essentially barrierless (i.e.,
a barrier height of 0.8 kcal/mol with respect to D2 in
terms of total energy) and to be associated with a
charge transfer event (see the Supporting Information
for details). The resulting complex E1, exergonic by
48.8 kcal/mol from D2, could then undergo
dissociation of the desired S–C coupled product to
form complex F1 (overall downhill in energy by 8.2
ΔG (kcal/mol)
M2-TS-N2
Me
S
SCF3
Me
Me
S
SCF3
CF3
Me
CF3
Me
Me
M2-TS-N2
S
M2
9.3
S
F3CS SCF3
13.1
CF3
F3C
L1
N2
Me
Me
0.0
-0.8
Scheme 8. Energetics of radical addition of alkyl radical to
sulfur dimer. Free Energies [DLPNO-CCSD(T)/def2-
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.202100469
Advanced Synthesis & Catalysis
TZVPP//B3LYP-D3/def2-SVP-CPCM(DMSO)]
kcal/mol.
in
corresponding thiyl radicals) and its validation as an
intermediate for product formation (Figure 3, also see
the Supporting Information) prompted computation
of the barrier for SH2 reaction of alkyl radicals with
disulfide 16 (Scheme 8) as well as exploration of
routes which lead to the generation of thiyl radicals
(Schemes 9 and 10). Complexation of alkyl radical
with the sulfur dimer M2 (Scheme 8, Path D) occurs
with a cost of 9.3 kcal/mol with regard to the
separated species L1. The following SH2 transition
state (M2-TS-N2) has a barrier of 13.1 kcal/mol and
gives intermediate N2, which is essentially
isoenergetic to L1. These results reinforce the notion
that the sulfur dimer can serve as an intermediate
(2)
Decomplexation
of
D2 (Path
C,
Decomplexation Pathway), where dissociation of
DHP radical A2 liberates N-(trifluoromethylthio)-
phthalimide (B1), is slightly exergonic by 2.2
kcal/mol. Addition of the isopropyl radical to
phthalimide via B1-TS-K2 has a barrier of 20.0
kcal/mol. This implies that EDA complexation is not
only required for efficient formation of alkyl radicals
but also beneficial for C–S bond formation.
(3) The experimental observation of disulfide 16
(presumably generated through recombination of the
leading
to
product
formation.
Scheme 7. Energetics of ground state intermediates from light-mediated pathways to alkyl radical. Free Energies
[DLPNO-CCSD(T)/def2-TZVPP//B3LYP-D3/def2-SVP-CPCM(DMSO)] in kcal/mol. Distances are reported in
Å ngstroms.
Turning to our exploration of potential pathways
leading to thiyl radical formation, we initially sought
to compute the thermodynamics of SCF3 radical
generation initiated by SET between N-
405 nm and above (Figure 1), we did not explore
excited state pathways of phthalimide leading to thiyl
radical (similar to Path B in Schemes 5 and 6).
Furthermore, our TD-DFT calculations clearly
suggest that photoexcitation of the EDA complex
does not result in N–S bond cleavage and that C–C
bond scission occurs instead (Scheme 6A, Path C).
Therefore, two potential pathways leading to SCF3
radical from intermediate D2 were explored (Schemes
9 and 10). Interestingly, thiyl radical dissociation was
only obtained via intermediate D2’ and was not
isolated from D2. Homolytic cleavage of the SCF3
functional group (D2’-TS-O2) was found to have a
barrier of 19.2 kcal/mol relative to D2’ leading to
intermediate O2 endergonic by 3.6 kcal/mol. Upon
(trifluoromethylthio)phthalimide
(B1)
and
A1
photoexcited DHP
as done previously for alkyl
radical (Path A, Scheme 5). The free energy of the
anionic intermediate formed (B1-) post homolytic
cleavage of SCF3 from radical anion B2- (see Figure
S36 in the Supporting Information) was found to be
60.5 kcal/mol, which is higher than alkyl radical
formation by 2.8 kcal/mol, suggesting that the single
electron transfer pathway is unlikely the major
pathway to thiyl radical. As phthalimide was shown
experimentally to have little to no absorbance from
8
This article is protected by copyright. All rights reserved.

10.1002/adsc.202100469
Advanced Synthesis & Catalysis
inspection of the Mulliken charges of intermediates
D2’ and O2, it was found that dissociation of the SCF3
radical occurs in concert with charge transfer from
the DHP radical to the phthalimide core, forming
charge transfer complex O2 (see the Supporting
Information). Release of the SCF3 radical to form P1
was found to be slightly higher in free energy than O2
by 1.4 kcal/mol. Pyridine and phthalimide, the two
side products formed in this transformation, are then
liberated from complex P1 upon proton transfer
(similar
to
Scheme
7).
Scheme 9. Energetics of ground state intermediates from light-mediated pathways to alkyl radical. Free Energies
[DLPNO-CCSD(T)/def2-TZVPP//B3LYP-D3/def2-SVP-CPCM(DMSO)] in kcal/mol. Distances are reported in
Å ngstroms.
Scheme 10. Energetics of hydrogen atom transfer pathways from D2 which could lead to thiyl raadical. Free Energies
[DLPNO-CCSD(T)/def2-TZVPP//B3LYP-D3/def2-SVP-CPCM(DMSO)] in kcal/mol. Distances are in Å ngstrom
Because of the relatively large barrier of radical
dissociation directly from D2 (19.1 kcal/mol, Scheme
9), we also considered an alternative pathway
involving hydrogen atom transfer (HAT) to the
oxygen or the nitrogen atom in the phthalimide core
(Scheme 10). Rearrangement of D2 to the O–H
hydrogen-bonded complex Q2 is found to be 3.4
kcal/mol higher in energy. Subsequent HAT occurs
via a barrierless transition state (Q2-TS-R2) to
complex R2, which is essentially identical in energy
to D2. As indicated in Scheme 10, the free energy of
Q2-TS-R2 was found to be lower than that of
intermediate O2 (by 2.8 kcal/mol).
9
This article is protected by copyright. All rights reserved.

10.1002/adsc.202100469
Advanced Synthesis & Catalysis
A similar result was obtained for D2’’-TS-U2,
7 and 8). In line with the experimental efforts, these
calculations highlight the necessity of EDA-
complexation for efficient alkyl radical formation.
Upon photoexcitation, charge-transfer is followed by
homolytic C–C bond cleavage, which delivers the
alkyl radical. The subsequently formed radical
complex D2 plays a crucial role in the two
thermodynamically favorable pathways to product
formation: (1) SH2 reaction of D2 with alkyl radicals –
although the latter represents a reaction of two
transient species and might hence be less dominant
than (2) SH2 reaction of alkyl radicals with disulfide
16 (L1, Scheme 8),[29] which was validated
experimentally. Formation of 16 occurs via
combination of the corresponding thiyl radicals,
which are generated upon completion of charge
transfer in D2 (Schemes 9). An alternative
mechanistic scenario involving SH2 reaction of alkyl
radicals with N-(trifluoromethylthio)phthalimide (B1,
Scheme 7) was found to be both kinetically and
thermodynamically less favorable, but probably
represents a co-existing pathway that might even be
dominant in an early phase of the reaction, before
sufficient levels of disulfide 16 are accumulated.
which also has a free energy 0.3 kcal/mol lower than
its following intermediate U2 However, the total
.
energies were found and have barriers of 0.8 and 1.0
kcal/mol with respect to O2 and R2 using B3LYP-D3
with def2-TZVPP as the basis set, though the free
energies of these transition states were found to be
lower in energy by the corresponding intermediates
by 0.6 and 0.8 kcal/mol, respectively. Each transition
state also has a single imaginary frequency
corresponding to the indicated HAT event.
Dissociation of pyridine I1 gives S2 and is endergonic
by 1.3 kcal/mol. SCF3 radical dissociation via S2-TS-
T2 has a barrier of 18.4 kcal/mol relative to D2 and
gives intermediate T2, which is overall endergonic by
3.6 kcal/mol with respect to D2. Exploration of the
N–H HAT (D2’’-TS-U2) revealed a prohibitively large
barrier of 27.2 kcal/mol when compared to D2.
Intermediate U2 was found to be essentially
isoenergetic to the preceding transition state.
Dissociation of pyridine I1 costs 1.5 kcal/mol and
gives intermediate V2. Homolytic cleavage of the
SCF3 radical (V2-TS-W2) has a barrier of 4.9
kcal/mol relative to V2 and gives complex W2, which
is exergonic by 9.8 kcal/ mol with respect to D2.
For the acyl-DHP system, potential pathways for
radical generation were explored using similar
computations as for their alkyl counterparts (see the
Supporting Information). TD-DFT calculations
revealed that the lone acyl-DHP’s lowest lying singlet
excited state (Figure S12, A1-S1) absorbs at 433 nm
and, upon optimization (Figure S12, A1-S1’), shows
bond elongation of the acyl-DHP’s C–C σ-bond (1.55
to 1.65 Å ). This suggests that EDA complexation is
not required for the generation of acyl radicals under
these conditions. However, the free energy of EDA
Conclusion
In summary, we have developed a catalyst- and
additive-free
decarbonylative
trifluoromethyl-
thiolation of aldehydes under open-air conditions.
This abundant feedstock has not been previously
employed as a source of alkyl radicals to construct
C(sp3)–SCF3 and C(sp3)–SCN bonds, thus providing
a complementary approach to help increase chemical
space. This photochemical strategy is driven by
selective excitation of electron donor–acceptor
(EDA) complexes, stemming from the association of
1,4-dihydropyridines with N-(trifluoromethylthio)-
phthalimide, to trigger intermolecular SET events that
deliver reactive radical species under ambient
conditions. The synthetic utility is further
demonstrated through visible light-promoted radical
thiocyanation, thioesterification, and conjunctive 1,3-
complexation
between
acyl-DHP
and
N-
(trifluoromethylthio)phthalimide was found to be
exergonic by 1.2 kcal/mol when computed using
DLPNO-CCSD(T)
(Figure
S19).
TD-DFT
calculations on the corresponding EDA complex
(Figure S14, C1) suggest hypsochromic shifting of
the absorption spectrum from 433 to 418 nm – when
comparing the lowest lying singlet excited states with
significant absorbance of the noncomplexed acyl-
DHP (A1-S1) to that of the EDA complex (C1-S2).
Fast internal conversion to C1-S1 and relaxation of
this excited state also results in bond elongation of
the acyl-DHP’s C–C σ-bond from 1.55 to 1.63 Å . In
difunctionalization
of
[1.1.1]propellane. The
necessity for EDA complexation of the
dihydropyridine donor and phthalimide acceptor for
efficient alkyl radical generation was elucidated
through
a
combination
of
spectroscopic
combination,
these
results
indicate
that
measurements and high-level quantum mechanical
calculations [dispersion-corrected (U)DFT, DLPNO-
CCSD(T), and TD-DFT]. Specifically, computation
of subsequent ground state pathways revealed that
SH2 addition of the alkyl radical to the intermediate
radical EDA complex D2 is extremely exergonic and
photoexcitation of both the individual DHP and the
EDA complex are viable pathways for acyl radical
generation. However, given the large absorption
coefficient of the acyl DHPs under blue light (Figure
1, note the difference to their alkyl counterparts), it
appears likely that direct photoexcitation of the acyl
DHPs might predominate.
results in
a
charge transfer event, yielding
intermediates poised to undergo facile deprotonation.
Alternatively, product formation can occur through
SH2 reaction of alkyl radicals with disulfide 16,
which was observed experimentally, or with N-
Overall, computational investigations were
performed to elucidate both light-mediated generation
of alkyl radicals (Schemes 5 and 6) and subsequent
ground state pathways to product formation (Schemes
(trifluoromethylthio)phthalimide.
comprehensive case study provides a deeper
This
10
This article is protected by copyright. All rights reserved.

10.1002/adsc.202100469
Advanced Synthesis & Catalysis
inch), whereby the temperature was maintained at
approximately 24 °C via cooling with a fan. After
completion, the reaction mixture was taken to dryness and
then purified using an automated system (UV detector,  =
254 nm and 280 nm) with RediSep Rf Gold® silica gel
disposable flash columns (60 Å porosity, 20–40 µm) and
hexanes/EtOAc (0–10% EtOAc) as eluent.
understanding of photoactive EDA paradigms
involving phthalimide- as well as DHP-systems, and
exemplifies how such EDA manifolds can be treated
computationally.
Experimental Section
For detailed experimental procedures, optimization studies,
UV/vis spectroscopy, compound characterization, X-ray
crystallography, NMR spectra, and computational details,
please refer to the Supporting Information. CCDC-
2052602 contains the supplementary crystallographic data
for this paper. This data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
General procedure for trifluoromethylthiolation (Scheme
2)
To an 8 mL reaction vial (17 x 60 mm) equipped with a
magnetic stir bar was added 4-alkyl- or 4-acyl-1,4-DHP
(1.00 mmol, 2.0 equiv) and N-(trifluoromethylthio)-
phthalimide (2, 124 mg, 0.50 mmol, 1.0 equiv) in anhyd
acetone (2.5 mL, 0.2 M) under air. The vial was sealed
with a cap containing a TFE-lined silicone septum, and the
soln was irradiated using blue Kessil lamps (distance
lamp–vial ~1.5 inches, typically 4 h for acyl-DHPs and 24
Acknowledgements
h
for alkyl-DHPs), whereby the temperature was
The authors are grateful for financial support provided by
NIGMS (R35 GM 131680 to G.M.). Osvaldo Gutierrez
acknowledges the NIGMS (R35GM137797) for funding and
UMD Deepthought2, MARCC/BlueCrab HPC clusters, and
XSEDE (CHE160082 and CHE160053) for computational
resources. Shorouk O. Badir is supported by the Bristol-Myers
Squibb Graduate Fellowship for Synthetic Organic Chemistry.
maintained at approximately 24 °C via cooling with a fan.
After completion, the reaction mixture was taken to
dryness and then purified using an automated system (UV
detector,  = 254 nm and 280 nm) with RediSep® Rf silica
gel disposable flash columns (60 Å porosity, 40–60 µm) or
RediSep Rf Gold® silica gel disposable flash columns (60
Å porosity, 20–40 µm) and hexanes/EtOAc (0–10%
EtOAc) as eluent.
Alexander
Lipp
is
grateful
to
the
Deutsche
Forschungsgemeinschaft (DFG) for a postdoctoral fellowship (LI
3682/1-1). The NSF Major Research Instrumentation Program
(award NSF CHE-1827457), the NIH supplement awards
3R01GM118510-03S1 and 3R01GM087605-06S1, as well as the
Vagelos Institute for Energy Science and Technology supported
the purchase of the NMRs used in this study.
General procedure for thiocyanation (Scheme 3B)
To an 8 mL reaction vial (17 x 60 mm) equipped with a
magnetic stir bar were added 4-alkyl- or 4-acyl-1,4-DHP
(1.00 mmol, 2.0 equiv) and N-(thiocyano)phthalimide (6,
102 mg, 0.50 mmol, 1.0 equiv). The vial was sealed with a
cap containing a TFE-lined silicone septum and placed
under an inert atmosphere through evacuating and purging
with Ar three times via an inlet needle. At this point, anhyd
degassed acetone (2.5 mL, 0.2 M, sparged with Ar for 15
min) was added, and the reaction was irradiated using blue
Kessil lamps (distance lamp–vial ~1.5 inches), whereby
the temperature was maintained at approximately 24 °C via
cooling with a fan. The reaction mixture was taken to
dryness and then purified using an automated system (UV
detector,  = 254 nm and 280 nm) with RediSep Rf Gold®
silica gel disposable flash columns (60 Å porosity, 20–40
µm) and hexanes/EtOAc (0–10% EtOAc) as eluent.
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13
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Advanced Synthesis & Catalysis
FULL PAPER
Catalyst-Free Decarbonylative
Trifluoromethylthiolation Enabled by Electron
Donor–Acceptor Complex Photoactivation
Adv. Synth. Catal. Year, Volume, Page – Page
Alexander Lipp,‡ Shorouk O. Badir,‡ Ryan
Dykstra,‡ Osvaldo Gutierrez,* and Gary A.
Molander*
14
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