Visible-light-induced addition of carboxymethanide to styrene from monochloroacetic acid

Article abstract of DOI:10.3762/bjoc.16.38

Where monochloroacetic acid is widely used as a starting material for the synthesis of relevant groups of compounds, many of these synthetic procedures are based on nucleophilic substitution of the carbon chlorine bond. Oxidative or reductive activation of monochloroacetic acid results in radical intermediates, leading to reactivity different from the traditional reactivity of this compound. Here, we investigated the possibility of applying monochloroacetic acid as a substrate for photoredox catalysis with styrene to directly produce γ-phenyl-γ-butyrolactone. Instead of using nucleophilic substitution, we cleaved the carbon chlorine bond by single-electron reduction, creating a radical species. We observed that the reaction works best in nonpolar solvents. The reaction does not go to full conversion, but selectively forms γ-phenyl-γ-butyrolactone and 4-chloro-4-phenylbutanoic acid. Over time the catalyst precipitates from solution (perhaps in a decomposed form in case of fac-[Ir(ppy)₃]), which was proven by mass spectrometry and EPR spectroscopy for one of the catalysts (N,N-5,10-di(2-naphthalene)-5,10-dihydrophenazine) used in this work. The generation of HCl resulting from lactone formation could be an additional problem for organometallic photoredox catalysts used in this reaction. In an attempt to trap one of the radical intermediates with TEMPO, we observed a compound indicating the generation of a chloromethyl radical.

Full text of DOI:10.3762/bjoc.16.38

Visible-light-induced addition of carboxymethanide to styrene
from monochloroacetic acid
Kaj M. van Vliet, Nicole S. van Leeuwen, Albert M. Brouwer and Bas de Bruin*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2020, 16, 398–408.
Van ‘t Hoff Institute for Molecular Sciences, Faculty of Science,
University of Amsterdam, Science Park 904, 1098 XH Amsterdam,
Netherlands
doi:10.3762/bjoc.16.38
Received: 10 January 2020
Accepted: 05 March 2020
Published: 16 March 2020
Email:
Bas de Bruin* - b.debruin@uva.nl
This article is part of the thematic issue "Advances in photoredox
catalysis".
* Corresponding author
Keywords:
Guest Editor: T. Noël
ATRA; catalysis; chloroacetic acid; lactone; photoredox
© 2020 van Vliet et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Where monochloroacetic acid is widely used as a starting material for the synthesis of relevant groups of compounds, many of
these synthetic procedures are based on nucleophilic substitution of the carbon chlorine bond. Oxidative or reductive activation of
monochloroacetic acid results in radical intermediates, leading to reactivity different from the traditional reactivity of this com-
pound. Here, we investigated the possibility of applying monochloroacetic acid as a substrate for photoredox catalysis with styrene
to directly produce γ-phenyl-γ-butyrolactone. Instead of using nucleophilic substitution, we cleaved the carbon chlorine bond by
single-electron reduction, creating a radical species. We observed that the reaction works best in nonpolar solvents. The reaction
does not go to full conversion, but selectively forms γ-phenyl-γ-butyrolactone and 4-chloro-4-phenylbutanoic acid. Over time the
catalyst precipitates from solution (perhaps in a decomposed form in case of fac-[Ir(ppy)3]), which was proven by mass spectrome-
try and EPR spectroscopy for one of the catalysts (N,N-5,10-di(2-naphthalene)-5,10-dihydrophenazine) used in this work. The gen-
eration of HCl resulting from lactone formation could be an additional problem for organometallic photoredox catalysts used in this
reaction. In an attempt to trap one of the radical intermediates with TEMPO, we observed a compound indicating the generation of
a chloromethyl radical.
Introduction
Monochloroacetic acid is an industrially important compound, vat dye) [3], to pharmaceuticals (ibuprofen, glycine, malonates)
with applications ranging from thickening agents (carboxy- [4] (see Figure 1). Many reactions with monochloroacetic acid
methyl cellulose, E466) [1,2], herbicides (2,4-dichlorophenoxy- have been published. The production of basic building blocks
acetic acid), cosmetics (cocamidopropyl betaine), dyes (indigo like glycine [5] (>600 000 tons/year in China in 2015) and
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Beilstein J. Org. Chem. 2020, 16, 398–408.
Figure 1: A part of the industry around monochloroacetic acid.
diethyl malonate from monochloroacetic acid show the value of tion reactions [12-16]. Photoredox catalysis provides a way to
this compound as a starting material. Many reactions with generate radical intermediates from simple organic molecules
monochloroacetic acid, including the synthesis of glycine and by single-electron redox processes. Single-electron oxidation
diethyl malonate, are based on nucleophilic substitution of the can produce carbon-centered radicals from substrates such as
chlorine [6-10].
amines [17], alkenes [18], and carboxylates [19], or by
hydrogen-atom transfer to an oxidatively formed thiolate radical
In an attempt to find new synthetic applications of mono- [20]. Single-electron reduction produces carbon-centered radi-
chloroacetic acid we turned our attention to photoredox cataly- cals from, for example, aryl nitriles [21], carbonyl or imine
sis. We were inspired by the rebirth of visible light photoredox species [22], iodonium or diazonium salts [23], or halide
catalysis, induced by the work of Yoon, Stephenson and species [24].
MacMillan [11]. By selective excitation of an organic or
organometallic dye by visible light a species is formed that can The formation of radicals from halide species by photoredox ca-
act as a single-electron oxidant and single-electron reductant. In talysis has been widely studied. It has been applied as a mild
this way reactive radical intermediates can be formed catalyti- method for the dehalogenation of several compounds [25-27].
cally in situ, resulting in reactivity different from common two- In the light of photoredox catalytic C–C bond formation, its ap-
electron pathways. Photoredox catalysis reactivity is very dif- plication in the field of atom transfer radical addition (ATRA)
ferent from traditional redox reactions, and the same reactivity reactions is very important. Remarkably, this type of C–C bond
cannot be achieved by stoichiometric addition of both a reduc- formation became only popular in 2011, while the first exam-
tant and an oxidant to a reaction mixture (as that would lead to a ple was already published by Barton in 1994 [28].
rapid redox reaction between the oxidant and the reducing agent
instead of converting the substrate). Excitation of the photocata- Recently, Kokotos and co-workers published a visible light
lyst, on the other hand, allows continuous formation of low con- photoredox catalyzed lactone formation from iodoacetic acid
centrations of both oxidized and reduced radical forms of the and alkenes [29] (Scheme 1). In addition, it has been shown that
substrate(s), and the excited catalysts (and/or their oxidized/ monochloroacetic acid can be reduced by hydrated electrons
reduced forms) can perform both opposed redox events before [30,31]. The group of Goez developed a strategy for the
returning to their original oxidation state for re-excitation. If no photoredox generation of hydrated electrons and applied that
substrate is encountered during the lifetime of the excited state for the dehalogenation of monochloroacetic acid [32,33]. How-
the ground state is typically regenerated.
ever, to the best of our knowledge, a photoredox catalyzed ap-
plication of monochloroacetic acid without using a sacrificial
Such photogenerated radical intermediates can be useful for the electron donor is not known. Interestingly, monochloroacetic
formation of new C–C bonds. Previous works from our group acid also contains a carboxyl group that could perhaps be oxida-
presented cobalt-catalyzed radical cyclization and carbonyla- tively decarboxylated to generate a chloromethyl radical. In this
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Beilstein J. Org. Chem. 2020, 16, 398–408.
Scheme 1: Redox based activation of haloacetic acid.
study, we investigated the possibility of redox neutral, visible −2.1 V vs Fc/Fc+) [34] and [Cu(dap)2]Cl (E*ox= −1.8 V vs
light photoredox catalyzed C–C bond formation with mono- Fc/Fc+) are strong enough reducing agents in their excited states
chloroacetic acid.
to be oxidatively quenched by monochloroacetic acid. Based on
these data, we concluded that the visible-light-promoted reduc-
tive photoredox C–C bond coupling reaction with mono-
Results and Discussion
First, we used cyclic voltammetry to determine the oxidation chloroacetic acid should be possible.
potential (EOx) of monochloroacetic acid in acetonitrile
(Figure 2). This way it could be verified, if monochloroacetic As such, we chose fac-[Ir(ppy)3] and [Cu(dap)2]Cl for the
acid can quench the excited state of one of the common photoredox reaction between monochloroacetic acid and
photoredox catalysts. In Figure 1 the cyclic voltammogram of styrene in acetonitrile under an atmosphere of N2 to form the
monochloroacetic acid is shown. One can see the onset poten- lactone 5-phenyldihydrofuran-2(3H)-one (and HCl) or the acid
tial for the reduction of monochloroacetic acid at −1.5 V vs 4-chloro-4-phenylbutanoic acid via an ATRA reaction
Fc/Fc+. The two photoredox catalysts, fac-Ir(ppy)3 (E*ox = (Scheme 2). The photoredox catalysts are excited by using blue
Figure 2: Cyclic voltammogram of monochloroacetic acid and ferrocene with 0.1 M [TBA][PF6] in MeCN. The potential is referenced to the Fc/Fc+
redox couple (0 V). The excited state reduction potentials of two different reducing photoredox catalysts (in red and green) are shown in the figure.
Scheme 2: Initial attempts for lactone formation by photoredox catalysis.
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LEDs with a peak excitation of 458 nm (see the experimental vs SCE in its excited state [35]). The weak C–H bond of aceto-
section for a detailed description) which is sufficient for the ex- nitrile (93.0 kcal mol−1) compared to the C–H bond strength of
citation of both complexes. For [Cu(dap)2]Cl, no product was a carbonyl α-C–H bond (94.1 kcal mol−1) resulted in formation
observed, but with fac-[Ir(ppy)3] we could observe the desired of 2 (2,2,6,6-tetramethylpiperidin-1-yl)oxyacetonitrile (com-
lactone, albeit in small amounts.
pound 2; Scheme 3) [36].
After these unsatisfying results we focused on the formation of Hence, to avoid the reaction with the solvent, we applied sol-
the carboxymethanide radical. We attempted trapping the vents with stronger C–H bonds (see Table 1). DMF and DMSO
radical by replacing styrene with TEMPO (2,2,6,6-tetra- are used frequently in the field of photoredox catalysis, but the
methylpiperidin-1-yl)oxyl). However, GC–MS analysis indicat- use of these solvents did not lead to formation of the desired
ed full conversion of TEMPO to the adduct resulting from a product either (Table 1, entries 2 and 3), using fac-[Ir(ppy)3] or
radical coupling between a cyanomethanide radical and [Cu(dap)2]Cl as the photosensitizer. Because the use of polar
TEMPO (Scheme 3) for the highly reducing [Ir(ppy)3] (−1.73 V solvents did not lead to the desired reactivity, we turned to non-
Scheme 3: The photoredox reaction of TEMPO with monochloroacetic acid catalyzed by fac-[Ir(ppy)3].
Table 1: Conditions screening for the photoredox catalyzed reaction between monochloroacetic acid and styrene.a
Exp.
Cat. loading
Solvent
ClAcOH (equiv)
Yield (1:3)
1
2
3
4
5
6
8
9
10
11
12
13
14
15
16
17
18
19b
20
21c
4%
4%
4%
4%
4%
4%
4%
4%
10%
3%
2%
1%
0.5%
4%
4%
4%
4%
4%
0%
4%
MeCN
DMF
DMSO
benzene
trifluoromethylbenzene
chlorobenzene
toluene
2
2
2
2
2
2
2
2
2
2
2
2
2
0.5
3
4
5
2
2
2
≈1% (1:0)
<1%
<1%
49% (1:3.0)
13% (1:4.4)
22% (1:3.3)
27% (1:4.7)
11% (1:1.3)
84% (1:4.3)
34% (1:2.8)
32% (1:2.2)
18% (1:1.3)
<1%
46% (1:2.8)
43% (1:3.3)
45% (1:3.1)
46% (1:2.8)
11% (1:1.2)
–
DCE
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
–
aA mixture of styrene (0.02 M), monochloroacetic acid and fac-[Ir(ppy)3] in solvent (2 mL) was irradiated overnight under a N2 atmosphere with
458 nm LEDs. The yield was determined by 1H NMR spectroscopy with trimethoxybenzene as external standard. b60 W fluorescent light bulb. cIn the
dark.
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polar solvents. Since [Cu(dap)2]Cl is insoluble in nonpolar sol- before consumption of all substrate. Unfortunately, because of a
vents, we continued with the more reducing fac-[Ir(ppy)3] lack of solubility, we were unable to analyze the precipitate. We
photocatalyst. The choice of benzene as a solvent led to a sig- also applied organic photoredox catalysts [37]. Miyake and
nificant formation of the desired lactone, according to GC–MS co-workers have introduced highly reducing organic
analysis. The 1H NMR and mass spectra of the crude reaction photoredox catalysts [38-43]. The use of 5,10-di(naphthalen-2-
mixture also demonstrated the formation of the ATRA product yl)-5,10-dihydrophenazine or 3,7-di(biphenyl-4-yl)-10-(naph-
4-chloro-4-phenylbutanoic acid. The two products were ob- thalen-1-yl)-10H-phenoxazine instead of [Ir(ppy)3] as the
tained in a combined yield of 49% (Table 1, entry 4). A further photoredox catalyst had no beneficial effect on the yield or
screening of nonpolar solvents did not lead to any significant conversion, and also led to the formation of a precipitate. How-
increase of the yield or selectivity (Table 1, entries 5–9).
ever, the precipitate that was formed when the organic dye
5,10-di(naphthalene-2-yl)-5,10-dihydrophenazine was used
The reduction of catalyst loading resulted in a lower yield and a proved to be soluble in DMSO, allowing us to characterize the
lower selectivity for the acid compound 3 (Table 1, entries material. After we discovered that the redissolved precipitate
10–14). The products indicate an oxidative quenching of the was NMR-silent, a room temperature EPR spectrum was re-
photoredox catalyst by reduction of the carbon chlorine bond of corded (Figure 3). The multiplicity in this spectrum is in agree-
monochloroacetic acid. Varying the stoichiometry of substrates ment with formation of the 1e-oxidized form of the organic
also did not lead to any improvement of the yield (Table 1, photocatalyst, showing hyperfine interactions with two equiva-
entries 15–18), most likely because the fac-[Ir(ppy)3]+ complex lent nitrogen nuclei (giso = 2.0032; ANiso = 18.6 MHz). The
(+0.77 V vs SCE) is unable to oxidize styrene sufficiently. In HRMS of this species showed the mass of the catalyst, thus
the absence of the photoredox catalyst or light, the reaction does confirming that the oxidized catalyst precipitates as a salt from
not take place (Table 1, entries 19 and 20).
solution when using benzene as a solvent.
Notably, during the reaction, the bright yellow color of the solu- Based on the formation of the cation of the photoredox catalyst,
tion resulting from the absorption of the catalyst disappears and we believe that after oxidative quenching the catalyst is not
an insoluble precipitate is formed. The use of C6D6 as a solvent fully reduced back to the neutral complex, accumulates in solu-
allowed us to directly measure the 1H NMR spectrum of the tion and as a result precipitates as chloride salt (with Cl− stem-
crude reaction mixture. The presence of both monochloroacetic ming from the substrate). We assume that the same happens
acid and styrene in this mixture is another indication that the when using the fac-[Ir(ppy)3] photocatalyst (vide supra; al-
catalyst had decomposed or precipitated from the solution though for the precipitate generated from this catalyst we were
Figure 3: EPR spectra measured (black) and simulated (red) based on the structure of the oxidized photoredox catalyst shown on the right.
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Beilstein J. Org. Chem. 2020, 16, 398–408.
unable to redissolve the solids for characterization). Also here tested in an attempt to form an iodo intermediate which was ex-
the catalyst is likely to precipitate as [Ir(ppy)3]Cl, but for this pected to cyclize more easily to the lactone [44]. However, the
photocatalyst additional deactivation pathways could also play a lack of solubility of these reagents in benzene likely hampered
role. For every lactone product that is formed, HCl is generated nucleophilic substitution and resulted in very low yields. Sodi-
and in the case of fac-[Ir(ppy)3], the acid could potentially um ascorbate was also added to investigate whether a sacrifi-
cause protodemetalation. This protodemetalation could be even cial electron donor could increase the yields, but this was not
more pronounced in the excited state (which is after all a metal- observed. Interestingly, the reaction with sodium ascorbate
to-ligand charge-transfer state). Therefore, we focused on favored the formation of lactone 1 over linear acid 3. The exact
methods to trap the HCl from solution (see Table 2). An addi- reason for this behavior is not clear, but perhaps ascorbate acts
tion of 2,6-lutidine as a base leads to a lower conversion. Al- as a weak base favoring lactone formation without deproto-
though the addition of a base is an efficient method to remove nating monochloroacetic acid.
HCl, deprotonation of monochloroacetic acid leads to an anion-
ic species that is harder to reduce. However, the use of 2,6-luti- In another attempt to avoid the formation of HCl we applied
dine gave a 32% yield. This could be caused by the reduced methyl chloroacetate. Hereby the formation of the lactone is
Brønsted base strength in apolar solvents. Thus, to avoid using inaccessible and HCl cannot be formed. However, when using
a base that deprotonates monochloroacetic acid, we added sodi- this substrate only 13% of the ATRA product were observed.
um chloroacetate to capture HCl from the reaction. However, Hence, there thus seems to be a positive effect of the acid on the
under these conditions the desired product was not formed at activation of the C–Cl bond. The precise mechanism of this re-
all. Addition of [Ag]PF6 to remove the chloride and solubilize ductive cleavage is currently unclear. Besides the direct reduc-
the oxidized photocatalyst also did not lead to any product for- tion of a carbon chlorine bond by electron transfer into the C–Cl
mation. [Ag]PF6 is poorly soluble in benzene and the Ag+ ion is antibonding orbital (Scheme 4A), the same intermediate can
likely to act as an oxidizing agent quenching the excited state of be formed by fragmentation of an α-haloketyl radical
the photocatalyst. Another additive we tried was tetrabutylam- (Scheme 4B). The acidic environment could lead to easier for-
monium hexafluorophosphate, thought to precipitate [TBA]Cl mation of this ketyl radical. Intuitively, pathway B seems most
and to keep [Ir(ppy)3]+ in solution as the PF6− salt. However, probable.
performing the reaction in the presence of [TBA]PF6 led to a
decreased yield. The use of diphenylurea to trap Cl− did not The reaction in benzene forms mainly the acid product 3 origi-
lead to a significant increase of the reaction yield either. In ad- nating from an ATRA reaction. We propose that this product is
dition, sodium iodide and tetrabutylammonium iodide were formed by radical propagation followed by a mechanism first
Table 2: Additive screening for the photoredox reaction between styrene and monochloroacetic acid.a
Exp
Additive
Yield (1:3)
1b
2
2,6-lutidine
[Ag]PF6
32% (1:2.2)
<1%
3
4
5
6
7
8
9c
10c
[TBA]PF6
29% (1:3.8)
<1%
50% (1:5)
3% (1:0)
≈1% (1:0)
39% (1:0.75)
12% (1: 0.75)
31% (1:2.5)
sodium chloroacetate
diphenylurea
sodium iodide
tetrabutylammonium iodide
sodium ascorbate
MeOH
acetic acid
aA mixture of styrene (0.02 M), monochloroacetic acid (2 equiv), fac-[Ir(ppy)3] and an additive (2 equiv) in benzene (2 mL) was irradiated overnight
under an N2 atmosphere with 458 nm LEDs. The yield was determined by 1H NMR spectroscopy with trimethoxybenzene as external standard.
b0.5 equiv of monochloroacetic acid were used. cAdditive as a cosolvent (10%).
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Beilstein J. Org. Chem. 2020, 16, 398–408.
chloroacetic acid or both. We did not see any formation of the
lactone (1) after irradiating the mixtures overnight with 458 nm
LEDs. Therefore, it is unlikely that in benzene direct conver-
sion from 3 to 1 plays any significant role under the applied
reaction conditions. The photoredox activation of mono-
chloroacetic acid leads to the formation of precipitate during the
reaction (see Figure 4), again indicating catalyst precipitation/
deactivation.
Scheme 4: Two possible acid-assisted, reductive activation pathways
of monochloroacetic acid (A–H = acid).
found by Kharasch and co-workers, where the benzyl radical
formed after addition of the generated α-carbonyl radical
abstracts a chloride from monochloroacetic acid to obtain the
product and propagates the reaction [45]. In situ IR experi-
ments show an exponential grow for product formation, which
is indeed indicative of a radical propagation mechanism (see
Supporting Information File 1). In acetonitrile, a small amount
of lactone was formed and no desired acid. Therefore, we inves-
tigated the effect of polarity on the selectivity of the reaction by
mixing acetonitrile with benzene (Table 3). Based on the result
with pure acetonitrile as a solvent (Scheme 2 and Scheme 3),
we expected a lower yield with higher concentrations of aceto-
nitrile. Indeed, the yield decreased with increasing amounts of
Figure 4: Reaction mixtures after overnight irradiation of (A) 4-chloro-
4-phenylbutanoic acid (3) and fac-[Ir(ppy)3]; (B) 3, fac-[Ir(ppy)3] and
monochloroacetic acid; (C) 3; (D) 3 and monochloroacetic acid. In
none of the vials lactone 1 was formed.
acetonitrile. On the other hand, the selectivity for the formation Works in the group of Noël and others have revealed that flow
of the lactone increased by adding more acetonitrile [46].
chemistry can increase the rate and yield of photoredox reac-
tions significantly [47-53]. According to the law of
To evaluate if γ-phenyl-γ-butyrolactone (1) can be formed from Lambert–Beer, only the outer shell of a batch reactor (vial or
4-chloro-4-phenylbutanoic acid (3) in benzene we reacted irra- Schlenk flask) is excited efficiently. Hence, radical formation
diated mixtures of 3 with either the photoredox catalyst, mono- (and propagation) is only efficient within this illuminated shell.
Table 3: Screening of the effect of mixing acetonitrile in benzene on the photoredox reaction.a
Entry
% MeCN
Yield (1:3)
1
2
3
4
5
6
0
5
10
15
20
50
49 (1:3)
26 (1:1)
25 (1:0.79)
22 (1:0.46)
18 (1:0.28)
11 (1:0)
aA mixture of styrene (0.02 M), monochloroacetic acid (5 equiv), fac-[Ir(ppy)3] in a mixture of benzene and acetonitrile (2 mL) was irradiated overnight
under an N2 atmosphere with 458 nm LEDs. The yield was determined by 1H NMR spectroscopy with trimethoxybenzene as external standard.
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Beilstein J. Org. Chem. 2020, 16, 398–408.
We anticipated that in a flow setup using tubing with a small Kharasch-addition product was observed. The benzylic radical
internal diameter (0.71 mm) the photocatalyzed reaction path- resulting from radical addition to these styrene derivatives
ways could be more efficient. However, in this case, per- seems to be too electron poor for efficient oxidation induced
forming the reaction under flow conditions did not lead to better cyclization, thus resulting in a Kharasch-type radical propaga-
results. The reaction performed in a flow reactor led to a tion reaction as the main pathway. Upon increasing the electron
combined yield of 32% within 1 hour. Furthermore, as in a density by using 4-vinylanisole, we did see formation of the
normal reactor, we also observed formation of precipitate in the lactone product. When we used p-nitrostyrene, no formation of
flow setup, forming clusters of solids. These solids presumably the desired products was observed at all.
consist of the oxidized or otherwise deactivated photocatalyst.
Based on the results described above we propose the mecha-
More insight into the selectivity for either the formation of the nism shown in Scheme 6, in which monochloroacetic acid oxi-
lactone or the ATRA reaction was obtained by screening a datively quenches the excited photocatalyst (fac-[Ir(ppy)3]*).
small substrate scope of para-substituted styrene derivatives in The thus obtained reduced monochloroacetic acid loses Cl− to
the photocatalyzed reaction with monochloroacetic acid using give the carboxymethanide radical intermediate A. Addition of
fac-[Ir(ppy)3] as the photocatalyst (Scheme 5). For electron- this species to styrene results in benzyl radical intermediate B.
poor p-halogenated and p-trifluoromethylated styrenes no From here two pathways are considered. Species B can be
lactone formation took place in these reactions, and only the oxidized by the [Ir(ppy)3]+ species that is formed after oxida-
Scheme 5: Substrate scope of styrene derivatives in the photoredox reaction with monochloroacetic acid. Yields have been determined by 1H NMR
spectroscopy of the crude reaction mixture, using 1,3,5-trimethoxybenzene as the external standard.
Scheme 6: Proposed reaction mechanism.
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Beilstein J. Org. Chem. 2020, 16, 398–408.
tive quenching to regenerate the ground-state photocatalyst unsuccessful in obtaining cyclopropane derivatives (see experi-
together with the formation of the benzyl cation intermediate C. mental section).
Species C then cyclizes to give intermediate E, which releases
H+ to form the lactone product F. Alternatively, B forms the Conclusion
Kharasch-addition product D by chlorine atom abstraction from We have shown that it is possible to use monochloroacetic acid
another monochloroacetic acid molecule, thus forming a new to form two types of radicals with visible light photoredox ca-
radical species A. Capture of Cl− by intermediate C (dashed talysis. The reductive formation of the carboxymethanide
arrow) cannot be fully ruled out, but seems unlikely to compete radical could be used for lactone formation with styrene.
with ring closure to F for entropic reasons.
Benzene was found to be the best solvent for this reaction.
However, the reaction is associated with some unsolved prob-
All attempts to trap intermediate C using methanol or acetic lems. The carboxylic acid group seems to be advantageous for
acid as co-solvent (see Table 2) were unsuccessful and resulted the activation of monochloroacetic acid, but the apolar solvent
in lower yields, especially in the case of methanol, likely due to in combination with formation of HCl is likely to cause catalyst
the increased polarity of the reaction mixture. Additionally, to deactivation/precipitation. This effect is more pronounced if
provide evidence for oxidative quenching, we tried trapping the electron-poor styrenes are used. We also found indications that
carboxymethanide radical with TEMPO in benzene. We were a chloromethyl radical can be formed with photoredox catalysis
surprised to see that instead we trapped the chloromethyl radical from monochloroacetic acid, but we were not yet able to apply
(Scheme 7) which was not expected in the absence of any base such reactions in a productive manner, such as in cyclopropan-
and with a relatively poorly oxidizing photoredox catalyst such ation reactions.
as fac-[Ir(ppy)3]. It is known that under acidic conditions
TEMPO can disproportionate into [TEMPO]+ and TEMPO–H
[54-56]. [TEMPO]+ (+0.25 V vs Fc/Fc+ [56]) is a strong
Supporting Information
enough oxidant to oxidatively quench [Ir(ppy)3]* (−0.30 V vs
Supporting Information File 1
Fc/Fc+ [34]). However, the oxidizing power of [Ir(ppy)3]+
(+0.77 V vs SCE) is insufficient to oxidatively decarboxylate
an acetate intermediate (≈ +1.2 V vs SCE). Unexpected elec-
tron transfer pathways can be considered, such as the self-
decarboxylation that was previously observed for a
[Cl3CCO2H][O2CCl3] mixture [57].
Experimental details.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-16-38-S1.pdf]
Acknowledgements
We would like to thank Ed Zuidinga for measuring mass spec-
tra and Tijmen Bakker for recording the emission spectra of the
light sources used in this work. We would like to thank Paul
Kuijpers and Sander Woutersen for useful discussions regarding
the IR spectroscopy measurements.
Inspired by the result above on decarboxylative activation we
anticipated its possibilities in cyclopropanation. The chloro-
methyl radical generation by photoredox catalysis is a useful
strategy for cyclopropanation [58]. Most photoredox catalyzed,
decarboxylative generations of carbon-centered radicals are
based on the formation of “stabilized” α-amino [59-65] or Funding
benzyl [66-70] radical species. However, the generation of This research was supported by The Netherlands Organization
unstabilized alkyl radical species is also known [71-74]. Based for Scientific Research (NWO), the Holland Research School of
on these observations and considerations, we attempted to use Molecular Chemistry (HRSMC), the UvA Research Priority
monochloroacetic acid as a precursor for cyclopropanation. We Area “Sustainable Chemistry” and the Advanced Research
have screened a series of strongly oxidizing photoredox cata- Center Chemical Building Blocks Consortium (ARC-CBBC
lysts and various alkenes, but unfortunately we were thus far project number 2019.021.A).
Scheme 7: The photoredox formation of 1-(chloromethoxy)-2,2,6,6-tetramethylpiperidine.
406

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