Mechanistic Investigation of the Formation of Isoindole N-Oxides in the Electron Transfer-Mediated Oxidative Cyclization of 2′-Alkynylacetophenone Oximes

Article abstract of DOI:10.1021/acs.joc.0c02318

This paper describes a joint experiment-theory investigation of the formation and cyclization of 2′-alkynylacetophenone oxime radical cations using photoinduced electron transfer (PET) with DCA as the photosensitizer. Using a combination of experimental 1H and 13C nuclear magnetic resonance (NMR) spectra, high-resolution mass spectrometry, and calculated NMR chemical shifts, we identified the products to be isoindole N-oxides. The reaction was found to be stereoselective; only one of the two possible stereoisomers is formed under these conditions. A detailed computational investigation of the cyclization reaction mechanism suggests facile C-N bond formation in the radical cation leading to a 5-exo intermediate. Back-electron transfer from the DCA radical anion followed by barrierless intramolecular proton transfer leads to the final product. We argue that the final proton transfer step in the mechanism is responsible for the stereoselectivity observed in experiment. As a whole, this work provides new insights into the formation of complex heterocycles through oxime and oxime ether radical cation intermediates produced via PET. Moreover, it represents the first reported formation of isoindole N-oxides.

Full text of DOI:10.1021/acs.joc.0c02318

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Article
Mechanistic Investigation of the Formation of Isoindole N‑Oxides in
the Electron Transfer-Mediated Oxidative Cyclization of 2′-
Alkynylacetophenone Oximes
Wan Shin Kim, Victor M. Espinoza Castro, Amanda Abiad, Michael Ko, Ashley Council, Anh Nguyen,
Laura Marsalla, Vicky Lee, Thao Tran, Andrew S. Petit,* and H. J. Peter de Lijser*
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ABSTRACT: This paper describes a joint experiment−theory investigation of the
formation and cyclization of 2′-alkynylacetophenone oxime radical cations using
photoinduced electron transfer (PET) with DCA as the photosensitizer. Using a
1
combination of experimental H and 13C nuclear magnetic resonance (NMR) spectra,
high-resolution mass spectrometry, and calculated NMR chemical shifts, we identified
the products to be isoindole N-oxides. The reaction was found to be stereoselective;
only one of the two possible stereoisomers is formed under these conditions. A detailed
computational investigation of the cyclization reaction mechanism suggests facile C−N
bond formation in the radical cation leading to a 5-exo intermediate. Back-electron
transfer from the DCA radical anion followed by barrierless intramolecular proton
transfer leads to the final product. We argue that the final proton transfer step in the mechanism is responsible for the
stereoselectivity observed in experiment. As a whole, this work provides new insights into the formation of complex heterocycles
through oxime and oxime ether radical cation intermediates produced via PET. Moreover, it represents the first reported formation
of isoindole N-oxides.
formed) as well as regiospecific when using 2′-aryl groups with
meta-substituents.
INTRODUCTION
■
Oxime-derived compounds have a broad range of applications
such as industrial chemicals,1−3 pharmaceuticals,4−8 and
antidotes for nerve gas poisoning.9−12 Because oximes and
oxime ethers contain two heteroatoms, they are popular
reagents for the synthesis of heterocycles, including natural
products and pharmaceuticals via intermolecular and intra-
molecular reactions.13−21 We have previously reported on the
use of 2′-arylbenzaldehyde oxime ethers as precursors for the
synthesis of phenanthridine derivatives under photoinduced
electron transfer (PET) conditions.22 This work was based on
the observation that oxime ether radical cations underwent
intermolecular nucleophilic attack at the nitrogen,23 whereas
oximes did not show such reactivity but instead formed the
corresponding carbonyl or nitrile via the proposed iminoxyl or
iminoyl radicals.24,25 The intermediate oxime radical cations
are highly acidic and quickly lose a proton to form an iminoxyl
radical, which might be more prone to react with a built-in
radical trap.22,26,27 Our initial study on the oxidative cyclization
reactions of oximes and oxime ethers showed that built-in
aromatic rings behaved as nucleophiles reacting with the
nitrogen atom of the oxime ether moiety.22 Because the oximes
did not show such reactivity, it was proposed that aromatic
rings do not act as radical traps. Unlike photochemical or
metal-catalyzed reactions of similar substrates, the PET
reaction was found to be selective (no nitrile byproduct was
To further explore the scope and limitations of oxidative
cyclization reactions of oximes and oxime ethers under
photoinduced electron transfer conditions, we have expanded
our studies to investigate the behavior of the alkyne moiety as a
nucleophile or a radical trap. Scheme 1 below summarizes the
possible cyclization pathways under these specific assumptions.
The alkyne moiety is expected to behave as a nucleophile in
the case of radical cation intermediates, which would possibly
lead to intermediate structures I or II. Alternatively,
deprotonation of the oxime radical cation prior to nucleophilic
attack by the alkyne will result in an iminoxyl radical, which
may react with the alkyne moiety (as a radical trap) to yield
cyclic structures such as III and IV.
Several groups have reported on the transformations of
ortho-alkynylaryl oxime derivatives, including various metal-
catalyzed processes.28−35 In general and ignoring follow-up
reactions, the main products observed in these types of
Received: September 29, 2020
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© XXXX American Chemical Society
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Scheme 1. Possible Exo and Endo Cyclization Pathways of Oxime Radical Cations and Iminoxyl Radicals with the Built-In
Alkyne Group Acting as a Nucleophile or Radical Trap
Figure 1. Structure of oxime and oxime ether substrates used in the photooxidative cyclization studies.
intramolecular cyclization reactions include isoquinoline N-
oxides,28−32 isoindoles,33 isoquinolines,34 isoquinolin-1(2H)-
ones,34 or indoles.35
Early reports showed the formation of isoquinoline N-oxides
from o-alkynyl oximes using an acid catalyst and heat.28,29
In the presence of cyanuric chloride, a Lewis acid (InCl3),
and a cocatalyst (PdCl2(MeCN)2), Wu and co-workers
observed a Beckmann rearrangement/intramolecular cycliza-
tion reaction of ketoximes that resulted in the formation of
substituted indoles.35
Under similar conditions, the methyl oxime ether was found to
produce an isoquinoline product.
Wu and Ding demonstrated the formation of functionalized
isoquinoline N-oxides via electrophilic cyclization of o-
alkynylbenzaldehydes with various electrophiles.30
Given the differences that we observed between the metal-
catalyzed cyclization reactions36−38 and the oxidative cycliza-
tion reactions of the 2′-arylbenzaldehyde oxime ethers under
PET conditions,22 we set out to investigate the behavior of
alkyne groups in a set of ortho-alkynyl benzaldehyde and
acetophenone oximes and oxime ethers under PET conditions
(see Figure 1). Our recent work has shown that radical cation
intermediates are easily generated when using oxime ethers
and 9,10-dicyanoanthracene (DCA) as the sensitizer22 or with
chloranil (CA) as the sensitizer.24,26,27 However, previously, we
have proposed that using CA as a sensitizer in the PET
reactions of oximes results in the formation of iminoxyl
radicals, presumably because the CA radical anion is a basic
species and aids in the deprotonation of the oxime radical
cation (as seen by formation of the semiquinone radical under
those conditions).27 Alternatively, because the DCA radical
anion is not a strong base, using DCA as the photosensitizer
could allow us to generate the oxime radical cations without
facilitating the deprotonation step. This in turn would increase
the lifetime of the radical cation intermediate, allowing for
nucleophilic attack by the alkyne moiety. As such, we have
carried out a series of preliminary studies to look at the effect
of the sensitizer in these reactions. Furthermore, we have
carried out blank experiments to eliminate any reactions that
are due to direct light absorption by the oximes or oxime
ethers. The results of these studies, combined with an in-depth
theoretical analysis of the mechanistic aspects of these
reactions, suggest the formation of a different product, an
isoindole-N-oxide, which, to the best of our knowledge, is the
first reported formation and isolation of this type of species.
Similar reactions were reported by Yamamoto and co-
workers.31
Shin and co-workers demonstrated the use of different
transition metal catalysts for the formation of quinoline N-
oxides from o-alkynyl oximes via 6-endo-dig N attack of the
(E)-oxime.32
It was found that when using the Z-isomer of the oxime, the
reaction produced predominantly or exclusively an isoindole
product.33
Zhang and Gao observed an interesting substituent effect in
the silver(I)-catalyzed cyclization reaction of o-alkynyl
benzaldehyde oxime derivatives, resulting in the formation of
isoquinolines or isoquinolin-1(2H)-ones, depending on the
oxime ether group.34
B
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no indication of cyclization or other product formation. When
the reaction was done with chloranil (CA) as the sensitizer at
350 nm (entry 2), the only reactivity observed was E/Z
isomerization (as confirmed by the same reaction without CA
present). Previously, we have observed that reactions of oximes
and oxime ethers derived from aldehydes react slower than
those derived from ketones.23−27 Our next step, therefore, was
to look at the reactivity of the corresponding acetophenone
oxime ether (2). Reacting oxime ether 2 with DCA at 420 nm
(entry 4) did not result in any significant product formation;
again, degradation of the starting material was the main
pathway. The same reaction with CA at 350 nm (entry 4)
showed minor E/Z isomerization. Given the differences
between the observed reactivities of the 2′-biaryl oxime
ethers22 and the o-alkynyl benzaldehyde and acetophenone
oxime ethers, it seems evident that the alkyne moiety behaves
differently compared to the aromatic ring.
RESULTS AND DISCUSSION
■
Optimization of the Oxidative Cyclization Pathway.
The desired alkynyl benzaldehydes and acetophenones as well
as their oxime and oxime ether derivatives (Figure 1) were
prepared according to standard literature methods with minor
modifications.37,38 Reactions were carried out on a small scale
in NMR tubes using deuterated solvents in order to follow the
reactions by NMR. Samples were also analyzed by GC−MS or
LC−MS spectrometry to verify product formation.
To explore the use of the alkyne moiety as a nucleophile or a
radical trap in the oxidative cyclization pathways of o-alkynyl
benzaldehyde and acetophenone oximes and oxime ethers,
conditions that were successful for similar reactions of 2′-biaryl
oxime ethers were attempted first.22 Irradiation of an
acetonitrile solution containing oxime ether 1 and 9,10-
dicyanoanthracene (DCA) as the sensitizer at 420 nm (Table
1, entry 1) resulted in degradation of the starting material with
In order for the oxidative cyclization to be successful, the
radical cation intermediate must have a significant lifetime,
which is why the use of oxime ethers was successful in the
previous study.22 Oxime radical cations are highly acidic and
generally deprotonate quickly,39,40 which typically prohibits
attack by the built-in nucleophile. Deprotonation of the oxime
radical cation yields an iminoxyl radical, which may react with
a radical trap. To determine whether the alkyne moiety reacts
as a radical trap rather than a nucleophile under these
conditions, we prepared the o-alkynyl benzaldehyde and
acetophenone oximes (3 and 4a−c) and subjected them to
the PET conditions described above. To promote formation of
the iminoxyl radicals, the reactions were carried out with
chloranil (CA) as the sensitizer. The CA radical anion is
known to be basic,23−27 and spectroscopic studies have shown
the formation of the semiquinone radical via proton transfer
from an oxime radical cation to the CA radical anion.27
Irradiation of oxime 3 at 350 nm in the presence of CA (Table
1, entry 7) resulted in the formation of new signals in the
NMR spectrum. When the same reaction was done in the
absence of CA, the same new signals were observed in the
NMR spectrum, suggesting that these new signals were due to
E/Z isomerization of the oxime. In the presence of DCA,
oxime 3 did not show any reaction when irradiated at 420 nm.
Table 1. Summary of the Photooxidation Reactions
Performed in This Study along with Their Outcomes
a
entry
oxime/oxime ether
sensitizer
λ (nm)
outcome
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1
1
1
2
2
2
3
3
DCA
CA
420
350
350
420
350
350
350
350
420
350
350
420
420
420
degradation
isomerization
isomerization
degradation
isomerization
isomerization
isomerization
isomerization
no reaction
isomerization
isomerization
cyclization
DCA
CA
CA
3
DCA
CA
4a
4a
4a
4b
4c
DCA
DCA
DCA
cyclization
cyclization
a
The light output consists of a range of approximately 100 nm
centered around the maximum output observed near either 350 nm
(CA) or 420 nm (DCA).
Figure 2. 1H NMR spectra at 400 Hz of oxime 4a with DCA in CD3CN upon irradiation at 420 nm for (a) 0 and (b) 2 h. Signals growing in (at
7.98, 7.70, and 7.19 ppm) are marked with an asterisk. Isolated reaction product (c) showing signals that are consistent with the ingrowing signals.
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Scheme 2. Exo Cyclization (Right) and Endo Cyclization (Left) Pathways of o-Alkynylacetophenone Oxime Derivatives
Scheme 3. Potential Products of the DCA-Catalyzed Photooxidative Cyclization of o-Alkynylacetophenone Oxime Derivatives
1
for the Identification of Possible H NMR Coupling Patterns
Table 2. Summary of Expected Splitting Patterns (s = Singlet; d = Doublet; t = Triplet; m = Multiplet) for the Potential Exo
and Endo Products Derived from Photooxidative Cyclization Reactions of Oximes 4a−c
Even after 4 h of irradiation, only a small amount of
isomerization was observed. Irradiation of oxime 4a at 350
nm (with or without CA) again resulted in isomerization of the
starting material; however, when the oxime was irradiated at
420 nm in the presence of DCA (entry 12), several new signals
(at 7.98, 7.70, and 7.19 ppm) were found to grow in over time,
whereas the oxime signal (9.17 ppm) disappeared (Figure 2).
After 2 h of irradiation, the conversion of the starting material
into the new product was clear and fairly clean, but prolonged
irradiation complicated a more detailed analysis of the reaction
mixture.
isomerization. Similarly, the new signals did not belong to the
corresponding ketone compound, leaving cyclization as a
potential pathway. A larger scale photolysis experiment allowed
for isolation of the product (Figure 2c), which demonstrated
that the peaks seen growing in belonged to the unknown
product.41 High-resolution mass spectrometry suggested no
change in molecular formula for the product, consistent with
the formation of a cyclic species via an intramolecular pathway,
but complete characterization was not possible from the NMR
and MS data.
Based on the existing literature of metal-catalyzed cyclization
reactions of o-alkynyl benzaldehyde and acetophenone
oximes,13−21 as well as the previous work from our lab,
which has suggested that the two main pathways involve
Comparison of the signals seen in the reaction mixture
(Figure 2b; t = 2 h) to those of the same reaction with CA at
350 nm shows that the new signals are not due to E/Z
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Figure 3. 1H NMR spectra at 400 Hz of the aliphatic region of oxime 4b with DCA in CD3CN upon irradiation at 420 nm for (a) 0 and (b) 2 h.
Signals growing in (at 0.95, 1.64, and 2.76 ppm) are marked with an asterisk. Attempts to isolate the reaction product were unsuccessful.
Figure 4. 1H NMR spectra at 400 Hz of the aliphatic region of oxime 4c with DCA in CD3CN upon irradiation at 420 nm for (a) 0 and (b) 2 h.
Signals growing in (at 3.39 and 2.29 ppm) are marked with an asterisk. Isolated reaction product (c) showing signals that are consistent with the
ingrowing signals.
nucleophilic attack on the radical cation and radical trapping,22
the main focus was on the 5-exo, 6-exo, 6-endo, and 7-endo
pathways and products. Considering the different cyclization
pathways and products that are possible (Scheme 2), it became
evident that different substrates would need to be tested to rule
out certain pathways and products.
Scheme 3 and Table 2 show that changing the phenyl group
on the alkyne to an alkyl group, such as butyl or isopropyl, will
allow us to distinguish between the endo and exo pathways. In
the case of the butyl and isopropyl derivatives, the exo
products would be expected to show coupling between the
alkenyl proton and the allylic protons. In particular, Table 2
shows that the alkenyl proton would be expected to be split
into a triplet or multiplet for the butyl derivative and into a
doublet or multiplet for the isopropyl derivative if an exo
product is formed. In contrast, in the endo products, this type
of coupling would be absent, and the alkenyl proton would be
a singlet (although long-range coupling cannot be ruled out
beforehand). It should be noted that each of the exo products
can exist as a cis or trans isomer (or a mixture); only the cis
isomers are shown in Scheme 3 and Table 2.
Irradiation of oxime 4b at 420 nm in the presence of DCA
again resulted in the formation of new signals that are
consistent with a cyclization pathway, similar to that of oxime
4a (Figure 3). Analysis of the aromatic region of the NMR
spectrum (Figure S1) shows the formation of a triplet signal
E
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1
1
Table 3. Comparison between the Experimental H NMR Chemical Shifts of Compound 5a with the Calculated H NMR
Chemical Shifts of 5-Exo and 6-Exo Molecular Geometries
1
1
1
1
1
proton
experiment H
5-exo cis calculated H
5-exo trans calculated H
6-exo cis calculated H
6-exo trans calculated H
bc
,
a
bc
,
bc
,
bc
,
number
region
(ppm)
(ppm)
(ppm)
(ppm)
(ppm)
22
15
19
20
21
17
18
16
23
alkenyl
aromatic
8.14 (1H)
7.64−7.60 (3H)
8.14
7.86
7.76 (2H)
7.51 (2H)
7.48
7.28
7.15
7.09
2.31 (3H)
7.22
7.59
9.14 (2H)
7.52 (2H)
7.58
7.32
7.21
7.27
2.39 (3H)
6.46
7.49
7.33 (2H)
7.25 (2H)
7.41
7.37
7.30
7.21
2.33 (3H)
6.11
7.64
7.89 (2H)
7.36 (2H)
7.53
7.39
7.35
7.18
2.32 (3H)
aromatic
aromatic
7.51−7.45 (3H)
7.35−7.28 (2H)
aromatic
methyl
7.17 (1H)
2.48 (3H)
a
b
The proton numbers are for the 5-exo cis geometry. The aromatic protons of the other geometries are ordered by chemical shift. The number of
c
equivalent hydrogens averaged together is given in parentheses. NMR isotropic shielding tensors were calculated at the mPW1PW91/6-
311+G(2d,p)//B3LYP/6-31+G(d,p) level of theory and converted into H chemical shifts using the calibration curve developed by Pierens.
42
1
(1H) at 7.04 ppm, which would be consistent with an aromatic
or olefinic proton coupling to a methylene group. The aliphatic
region (Figure 3) shows that the butyl group signals change
over time with new signals growing in at 0.95, 1.64, and 2.76
ppm. The growth of a new quartet (2H) at 2.76 ppm is clear,
and this splitting pattern would be most easily explained by a
product formed via an exo pathway, with coupling between the
allylic methylene protons and the olefinic exo proton. Attempts
to isolate the product from the reaction mixture were not
successful despite trying to do so under a variety of conditions.
Irradiation of oxime 4c in acetonitrile in the presence of
DCA at 420 nm shows the appearance of a doublet (1H) in
the aromatic region (6.88 ppm, Figure S2) and a multiplet
(1H) in the aliphatic region (3.39 ppm, Figure 4). HRMS
analysis of the isolated product confirmed the mass of the
alledged cyclic structure, but it is not possible to distinguish
spectra shown in Figures 3 and 4 and Figures S1−S5 suggest
that products 5a−5c are the result of an exo cyclization
pathway and distinct from the products of the Ag(I)-catalyzed
oxidative cyclization of compounds 4a−4c. However, they do
not unambiguously identify whether 5a−5c are the 5- or 6-exo
cyclization products. In order to better understand the
molecular structure of 5a−5c, we turn to the computational
1
prediction of the H and 13C NMR chemical shifts using the
computational approach described in the Computational
Methods. In order to first validate the chosen computational
approach, we analyzed the 1H and 13C NMR chemical shifts of
the isoquinoline N-oxide products 6a−6b as well as an
additional isoquinoline N-oxide from the literature,33 the
results of which are summarized in Tables S1−S6 in the
Supporting Information. For these compounds, the calculated
1H chemical shifts are all within 0.26 ppm of experiment,
whereas the calculated 13C chemical shifts are consistently
within 3.44 ppm of experiment. This analysis provides a
general sense of the accuracy that we can expect from the
calculated NMR chemical shifts for conjugated N-oxides.
Table 3 compares the calculated 1H NMR chemical shifts for
potential 5-exo and 6-exo product molecular geometries with
the experimental 1H NMR chemical shifts of 5a. The
optimized 5-exo and 6-exo molecular geometries with the
alkenyl hydrogen oriented cis with the N−O are shown in
Figure 5; the 5-exo and 6-exo trans isomers, shown in Figure
S9, have the phenyl group oriented cis with the N−O. The
number of equivalent protons that were averaged together in
the calculation of the chemical shifts is indicated in
parentheses.
1
between endo or exo products. Further analysis of the H
NMR spectrum shows that it is consistent with that of a
product formed via an exo cyclization pathway. The multiplet
at 3.39 ppm contains two coupling constants: 6.67 and 10.56
Hz; the doublet at 6.88 ppm has a coupling constant of 10.56
Hz, which is consistent with a proton coupling to two
equivalent methyl groups as well as a single olefinic (exo)
proton.
These results confirm the above observation that the most
likely explanation is an exo cyclization pathway to yield either
an isoindole N-oxide or benzo[d][1,2]oxazine. To further rule
out the endo pathways, we independently synthesized the
isoquinoline N-oxides 6a−b from oximes 4a−b32 and
1
confirmed from their H NMR spectra that they are not the
1
products formed in the PET reactions (Figures S3 and S4 in
the Supporting Information). We additionally subjected 4c to
the same conditions as were used to synthesize the
isoquinoline N-oxides 6a−b and confirmed that the resulting
Table 3 shows that the calculated H NMR chemical shifts
for the 5-exo cis isomer are consistently in good agreement
with experiment, with the largest discrepancy being 0.22 ppm.
1
In particular, the calculated H NMR chemical shift of the
1
product has a distinctly different H NMR spectrum (Figure
alkenyl proton for the 5-exo cis isomer is in excellent
agreement with experiment. In contrast, the calculated alkenyl
proton chemical shifts of the other three isomers exhibit large
discrepancies with experiment, being too low by 0.92, 1.68, and
2.03 ppm for the 5-exo trans, 6-exo cis, and 6-exo trans
isomers, respectively. It is important to note that the
discrepancy between the experimental alkenyl proton NMR
chemical shift and the calculated value for the 5-exo trans and
6-exo molecular geometries is significantly larger than the
S5) from the product formed through the PET reaction
(Figure 4 and Figure S2).
Because the NMR and HRMS could not distinguish
between the different exo products, we opted to further
explore these two pathways by means of density functional
theory in hopes of gaining a better understanding of the
mechanistic aspects of these oxidative cyclization reactions.
Computational Analysis of the 1H and 13C NMR
Chemical Shifts and Assignment of the 5a−5c Cyclized
Products. The analysis shown in Table 2 and the NMR
1
errors observed in the calculated H NMR chemical shifts for
the isoquinoline N-oxides (Tables S1−S6). As such, the data
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ppm. Note, though, that assignment of the experimental
alkenyl 13C chemical shift is tentative because the calculated
chemical shift of this carbon overlaps with the 13C chemical
shifts of other aromatic carbons.
Figures S10−S13 and Tables S7−S9 in the Supporting
Information summarize our comparison between the calcu-
1
lated and experimental H and 13C NMR chemical shifts of
products 5b and 5c. Throughout our analysis, we consistently
find that the calculated chemical shifts of the 5-exo cis
molecular geometry are in significantly better agreement with
the experimental spectra than the other possible exo products.
As above, this is especially true for the alkenyl proton and the
carbons that are adjacent to the N−O. The largest
discrepancies between the experimental chemical shifts of
5a−5c and the calculated chemical shifts of the 5-exo cis
geometry are 0.26 ppm for H and 3.91 ppm for 13C. Overall,
1
Figure 5. Optimized 5-exo (left) and 6-exo (right) molecular
geometries with the alkenyl hydrogen oriented cis to the N−O
group. The proton and carbon numbers referred to in Tables 3 and 4
are indicated. The geometries were optimized in the gas phase at the
B3LYP/6-31+G(d,p) level of theory.
our analysis based on the comparison of experimental and
calculated 1H and 13C NMR data strongly suggests that
products 5a−5c have 5-exo molecular structures with the
alkenyl hydrogen oriented cis to the N−O.
The Feasibility of Generating o-Alkynyl Oxime and
Oxime Ether Radical Cations through PET. With solid
support for the formation of products 5a−5c, we now turn to
understanding the mechanism through which they are formed,
beginning with the photooxidative formation of the oxime
radical cations through PET. Table 5 summarizes the
experimental oxidation potentials of compounds 1−3 and
4a−4c, along with the calculated change in free energy
associated with PET, ΔGET, with either DCA or CA as the
photosensitizer. For all compounds, ΔGET is less than 0, which
indicates that formation of the radical cation through PET is
spontaneous. When DCA is used as the photosensitizer, the
range of ΔGET values is consistent with effective PET based on
our previous study of the formation and intramolecular
cyclization of 2′-arylbenzaldehyde oxime ether radical
cations.22,43 When CA is used as the photosensitizer, the
ΔGET becomes even more negative. Based on our previous
work, the use of CA with compounds 1−4a results in ΔGET
presented here is most consistent with 5a being the 5-exo
product with the alkenyl proton cis to the N−O.
Further support for our assignment of the molecular
structure of 5a comes from the 13C NMR chemical shifts
compared in Table 4. Focusing on the most downfield peaks,
which are attributed to the two carbons that are adjacent to the
N−O, the calculated chemical shifts for the 5-exo cis structure
are in very good agreement with the experimental chemical
shifts of 5a, with differences of 0.28 and −0.06 ppm. In
contrast, the calculated 13C NMR chemical shifts for the 5-exo
trans and both 6-exo molecular geometries are significantly
further downfield than what is found in the experimental
spectrum, with discrepancies of 5.25, 13.87, and 12.35 ppm for
the 5-exo trans, 6-exo cis, and 6-exo trans molecular
geometries. Turning to the rest of Table 4, the calculated
chemical shifts of the 5-exo cis structure continue to be in good
agreement with experiment, with the largest error being 1.69
Table 4. Comparison between the Experimental 13C NMR Chemical Shifts of Compound 5a with the Calculated 13C NMR
Chemical Shifts of 5-Exo and 6-Exo Molecular Geometries
carbon
experiment 13C
(ppm)
5-exo cis calculated 13C
b c
5-exo trans calculated 13C
bc
6-exo cis calculated 13C
bc
6-exo trans calculated 13C
bc
a
,
,
,
,
number
region
(ppm)
143.07
(ppm)
148.04
(ppm)
156.66
(ppm)
155.14
12
N−O
142.79
adjacent
N−O
adjacent
alkenyl
11
141.38
141.32
139.33
149.32
150.01
13
5
10
9
7
3
8
6
2
1
129.70
134.87
133.02
129.84
129.83
128.92
128.85
128.16
126.71
121.83
119.22
9.76
131.13
135.59
133.70
130.83 (2C)
130.38
129.32
128.48 (2C)
126.52
126.22
120.73
117.53
9.84
128.75
136.65
132.65 (2C)
132.48
132.02
130.02
128.09 (2C)
127.99
126.20
118.03
117.17
110.63
136.43
131.88
129.71
128.57 (2C)
128.50
128.41 (2C)
126.63
125.82
102.45
135.82
133.37
129.43
128.87
128.69 (2C)
128.04 (2C)
125.37
124.82
122.09
120.26
17.36
aromatic
aromatic
aromatic
aromatic
aromatic
aromatic
aromatic
aromatic
aromatic
aromatic
methyl
124.15
123.78
17.14
4
14
10.68
a
b
The carbon numbers are for the 5-exo cis geometry. The aromatic carbons of the other geometries are ordered by chemical shift. The number of
c
equivalent carbons averaged together is given in parentheses. NMR isotropic shielding tensors were calculated at the B3LYP/6-311+G(2d,p)//
B3LYP/6-31+G(d,p) level of theory and converted into 13C chemical shifts using the calibration curve developed by Pierens.42
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Table 5. Experimentally Determined Oxidation Potentials (EOX), Free Energies of Photoinduced Electron Transfer with DCA
or CA as the Photosensitizer (ΔGET), and Calculated Ionization Potentials (IP) of Compounds 1−3 and 4a−4c
a
b
c
d
R1
R2
R3
Eox (V)
ΔGET (kcal mol−1
)
ΔGET (kcal mol−1
)
IP (kcal mol−1
)
1
2
3
4a
4b
4c
H
CH3
H
CH3
CH3
CH3
CH3
CH3
H
H
H
Ph
Ph
Ph
Ph
1.66
1.61
1.70
1.64
1.78
1.73
−6.9
−8.0
−5.9
−7.4
−4.1
−5.2
−10.6
−11.7
−9.6
−11.1
−7.7
147.22
147.59
147.02
147.76
151.75
152.65
CH2CH2CH2CH3
CH(CH3)2
H
−8.9
a
b
Oxidation potentials (half-wave potentials) obtained by cyclic voltammetry. Calculated free-energy changes for the one-electron transfer process
from the compounds to 1DCA* in acetonitrile by the application of the Rehm−Weller equation: the excited singlet energy of DCA, 2.90 eV, and
reduction potential of DCA, −0.91 V vs SCE.44,45 Calculated free-energy changes for the one-electron transfer process from the compounds to
c
3CA* in acetonitrile by the application of the Rehm−Weller equation: the excited triplet energy of CA, 2.13 eV, and reduction potential of CA, 0.02
V vs SCE.44,45 Calculated ionization potentials at the ωB97M-V/def2-QZVPP//ωB97X-D/cc-pvdz level of theory.43
d
values that lie deep in the Marcus inverted region where PET
will occur very slowly, if at all. This potentially explains why
only isomerization was observed when CA was used as the
photosensitizer with these compounds.
Focusing on compounds 4a−4c with DCA, the ΔGET of 4a,
−7.4 kcal/mol, is considerably more negative than the ΔGET of
4b and 4c, −4.1 and −5.2 kcal/mol, respectively. In order to
understand the cause of this, we analyzed the spin densities,
which indicate where the unpaired electron is localized in the
radical cation and hence where the oxidation primarily
occurred. The spin densities of the radical cations at the
neutral optimized geometries of 4a−4c are reported in Figure
S14 in the Supporting Information. For compounds 4b and 4c,
the spin density is found to be primarily localized on the
central benzene ring and alkynyl group, with little spin density
Figure 6. 5-Exo and 6-endo cyclization reaction coordinate diagrams
present on the oxime group. In contrast, for compound 4a, the
for the radical cation (solid blue line) and the iminoxyl radical
spin density is further delocalized into the phenyl group,
stabilizing the radical cation and hence lowering the oxidation
potential.
(dashed red line) of 4a. All free energies were evaluated at the RO-
ωB97M-V/def2-QZVPP//U-ωB97X-D/cc-pVDZ level of theory and
are reported relative to the lowest energy acyclic radical cation or
radical conformation.
Table 5 provides additional insights into the pattern of
reactivity summarized in Table 1. In particular, the fact that
compounds 1−3 all have ΔGET that are more negative than
those of 4b−4c suggests that compounds 1−3 can undergo
PET with DCA. As a result, the inability of compounds 1−3 to
undergo cyclization cannot be attributed to radical cation
formation but rather to subsequent steps in the mechanism.
Computational Analysis of the Radical Cation
Cyclization Mechanism. With the formation of the radical
cations discussed, we now consider their reactivity, focusing
first on the ketone oximes. Oxime radical cations are well-
known to be strongly acidic, and the compounds considered in
this study are no exception.39,40 Indeed, the calculated pKa
values for the 4a−4c radical cations range from −6.41 to
−9.81, suggesting that a large fraction of the radical cations
generated through PET will undergo deprotonation to form
iminoxyl radicals; further details may be found in Table S10 in
the Supporting Information. As such, we will consider the
possibility of both radical cation and iminoxyl radical
cyclization in our analysis.
coordinate diagram for the formation of the 5-exo
intermediates as both an iminoxyl radical (dashed red line)
and as a radical cation (solid blue line) for compound 4a. The
free energies are reported relative to the lowest acyclic
minimum energy geometry of the radical or radical cation,
both of which have the nitrogen of the oxime group oriented
toward the alkynyl group. The radical pathway for 5-exo
cyclization has a free-energy barrier of 13.1 kcal/mol and
results in an intermediate that is downhill in free energy by
−1.6 kcal/mol. In contrast, the radical cation has a very low
barrier for 5-exo cyclization of only 2.9 kcal/mol. Moreover,
the radical cation 5-exo intermediate is much lower in free
energy than the corresponding radical intermediate at −20.1
kcal/mol. For both the iminoxyl radical and the radical cation,
the 5-exo intermediate can exist in two isomers, which are
nearly isoenergetic and separated by a small, less than 1.5 kcal/
mol, barrier. Figures S15 and S16 in the Supporting
Information show very similar reaction coordinate diagrams
for the 5-exo cyclization of 4b and 4c, with 5-exo cyclization
more kinetically and thermodynamically favorable for the
oxime radical cation than for the iminoxyl radical. Indeed, 5-
According to our analysis of the NMR spectra, the most
likely cyclization pathway of compounds 4a−4c leads to the 5-
exo product (5a−5c) in each case. Figure 6 shows the reaction
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exo cyclization is uphill in free energy by 2−4 kcal/mol for the
iminoxyl radicals of compounds 4b and 4c.
the radical cation, 9.0−10.6 kcal/mol, and the radical, 3.2−5.2
kcal/mol. Collectively, Figures 6 and 7 and Figures S15−S18
show that C−O bond formation is less kinetically and
thermodynamically favorable than C−N bond formation for
compounds 4a−4c.
Figure 6 also displays the reaction coordinate diagram for 6-
endo cyclization, leading to 6a. This pathway has a higher
barrier than that leading to the 5-exo intermediate for both the
iminoxyl radical and the radical cation, 23.0 and 12.2 kcal/mol,
respectively. The 6-endo intermediate is similarly downhill in
energy compared to the 5-exo intermediate for both the
radical, −2.1 kcal/mol, and the radical cation, −18.7 kcal/mol.
Figures S15 and S16 show that for 4b and 4c, formation of the
6-endo radical cation intermediate is more thermodynamically
favorable than formation of the 5-exo radical cation
intermediate. However, the barrier for 6-endo cyclization
remains significantly larger than the barrier for 5-exo
cyclization. As such, Figure 6 and Figures S15 and S16 suggest
that 6-endo cyclization results in the thermodynamic product,
whereas 5-exo cyclization leads to the kinetic product.
In order to understand the difference in reactivity between
the radical cation and the radical, we analyzed the natural bond
orbital (NBO) spin densities and partial charges at the radical
and radical cation acyclic conformers with the oxime nitrogen
oriented toward the alkynyl group;46 this information is
summarized in Tables S11 and S12 in the Supporting
Information. For the radical compounds, the NBO spin
density is strongly localized on the N and O, with the N
becoming electrophilic due to its positive NBO partial charge.
In contrast, the NBO spin density of the radical cations is most
strongly localized on the alkynyl group, with little NBO spin
density localized on O. This is consistent with the spin density
distributions at the neutral optimized conformations shown in
Figure S14. For the 4b and 4c radical cations, the spin density
on the N is comparable in magnitude to that localized on the
alkynyl carbon closest to the oxime group, whereas for the 4a
radical cation, little spin density is localized on the N. For all of
the radical cations, the alkynyl carbons bear either positive or
slightly negative partial charges, whereas the NBO partial
charge on N is significantly more negative. Overall, the data
summarized in Tables S11 and S12 suggests that the reaction
coordinate diagrams are different for the radical and the radical
cation because of differences in how the unpaired electron is
distributed in the molecule. Moreover, both the radical cation
spin densities and charge distributions are inconsistent with
the alkynyl group acting as a nucleophile. Finally, note that for
the radical cations, the proton on the oxime group is calculated
to have a large NBO partial charge, 0.51 to 0.52, which is
consistent with the strong acidity of these oxime radical cations
shown in Table S10.
Overall, the cyclization pathway is most consistent with the
involvement of a radical cation intermediate and the formation
of the 5-exo products 5a−5c. Figure 6 demonstrates that the
kinetic as well as thermodynamic driving forces are both
significantly larger for radical cation cyclization than for radical
cyclization. Moreover, for the radical cations, cyclization must
compete with deprotonation, and because deprotonation is
thermodynamically very favorable, radical cation cyclization
must occur extremely rapidly to occur prior to deprotonation.
This provides an explanation for why 5a−5c are the kinetic 5-
exo cyclic products rather than the thermodynamic 6-endo
cyclic products.
Figure 7 shows the reaction coordinate diagram for forming
the 6-exo and the 7-endo intermediates as either a radical
Figure 7. 6-Exo and 7-endo cyclization reaction coordinate diagrams
for the radical cation (solid blue line) and the iminoxyl radical
(dashed red line) of 4a. All free energies were evaluated at the RO-
ωB97M-V/def2-QZVPP//U-ωB97X-D/cc-pVDZ level of theory and
are reported relative to the lowest energy acyclic radical cation or
radical conformation.
cation or an iminoxyl radical for compound 4a. Both the 6-exo
and 7-endo cyclization pathways begin from the acyclic Z-
isomer conformation with the oxime group oriented toward
the alkynyl group. For both the iminoxyl radical and the radical
cation, there is an energetic cost to reaching the Z-isomer of
the oxime group, which is necessary for C−O bond formation
to occur. Moreover, the calculated barriers for the E/Z
isomerization of the oxime group are 20.7 and 13.2 kcal/mol
for the radical cation and the iminoxyl radical of compound 4a,
respectively. 7-Endo cyclization is uphill in free energy for both
the radical and the radical cation and has a larger barrier than
6-exo cyclization. As a radical cation, 6-exo cyclization has a
free-energy barrier of 11.3 kcal/mol and results in a 6-exo
radical cation intermediate that is uphill in free energy by 9.2
kcal/mol. In contrast, as an iminoxyl radical, the 6-exo
intermediate is downhill in free energy by −3.0 kcal/mol but
separated from the acyclic conformation by a 17.8 kcal/mol
barrier. Figures S17 and S18 show that the reaction coordinate
diagrams associated with C−O bond formation as a radical
cation or an iminoxyl radical for 4b and 4c are similar to that
shown in Figure 6; the only major difference is that the 6-exo
intermediates of 4b and 4c are uphill in free energy for both
In Figure 8, we propose an overall mechanism for the PET-
induced cyclization of compounds 4a−4c. The initial steps in
this mechanism, radical cation formation through PET with
DCA and the subsequent intramolecular cyclization of the
radical cation to generate the radical cation 5-exo cyclic
intermediate, have been discussed above. The next step in the
proposed mechanism involves back-electron transfer from the
DCA radical anion to generate a neutral cyclic intermediate
and DCA. As the PET required an input of 2.90 eV of energy
to occur, this back-electron transfer will be thermodynamically
favorable. Moreover, as DCA was previously shown to act as a
catalyst in the photooxidative cyclization of 2′-arylbenzalde-
hyde oxime ethers,22 it is reasonable to suggest that it acts as a
catalyst in the photooxidative cyclization reaction studied here.
Finally, because the minimum-energy acyclic conformer of the
radical cation is already properly oriented for C−N bond
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ultimately lead to product formation. Figure S20 in the
Supporting Information shows that after back-electron transfer
with the DCA radical anion, the 5-exo trans neutral
intermediate will undergo C−N bond cleavage to regenerate
the starting material. This process is kinetically and
thermodynamically favorable; the barrier is 8.8 kcal/mol, and
regeneration of the starting material is downhill in free energy
by −18.5 kcal/mol for compound 4a; the process is even more
favorable for 4b and 4c. Likewise, Figure S21 shows that if the
6-endo radical cation intermediate is formed, then it will also
undergo spontaneous C−N bond cleavage to regenerate the
starting material after back-electron transfer makes it neutral;
the barrier is less than 15 kcal/mol for all three compounds,
and the C−N bond cleavage is downhill in free energy by
−14.2 to −15.9 kcal/mol.
The proposed mechanism of the radical cation cyclization of
compounds 4a−4c also explains why no product formation
was observed for the oxime ethers 1 and 2. As discussed above,
Table 5 shows that the ΔGET of compounds 1 and 2 is
consistent with radical cation generation when DCA is the
sensitizer. Likewise, our calculations suggest that radical cation
5-exo cyclization will occur; further details are shown in
Figures S22 and S23 in the Supporting Information. However,
formation of the final product now requires an intramolecular
methyl group transfer as opposed to an intramolecular proton
transfer. This methyl group migration is expected to have a
very high barrier, making it kinetically unfeasible. Instead, the
neutral 5-exo intermediate, formed after back-electron transfer
with the DCA radical anion, undergoes C−N bond
dissociation to regenerate the starting material; see Figure
S24 in the Supporting Information.
We finally consider why no product is observed with
compound 3. Table 5 shows that the ΔGET of compound 3 is
more negative than those of 4b and 4c, suggesting that
compound 3 will undergo PET with DCA. Figures S25 and
S26 in the Supporting Information suggest less favorable
radical cation cyclization kinetics for compound 3 than for
compound 4a. Specifically, Figure S26 shows that the two
acyclic radical cation conformers of 3 are essentially
isoenergetic with no significant thermodynamic driving force
to align the oxime and alkynyl groups for cyclization. In
contrast, the acyclic radical cation conformer of 4a with the N
oriented toward the alkynyl group is 1.98 kcal/mol lower in
energy than the other conformer. Moreover, the radical cation
5-exo cyclization barrier for 3 is higher than for 4a, 5.14 kcal/
mol versus 2.91 kcal/mol. Collectively, this suggests that the
radical cation form of compound 3 will require more time for
the oxime and alkynyl groups to align themselves and
subsequently cyclize than the radical cation form of compound
4a. This will make radical cation deprotonation more
competitive with cyclization for compound 3, potentially to a
large enough extent to explain the absence of the product with
this compound.
Figure 8. Proposed mechanism for the formation of isoindole N-
oxides from the photooxidative cyclization of 2′-alkynylacetophenone
oximes.
formation and the 5-exo cyclization barrier is very small, the
radical cation cyclization will occur extremely rapidly. As such,
it is possible that the 5-exo cyclic radical cation intermediate
can form before the DCA radical anion has had enough time to
diffuse away, further facilitating back-electron transfer.
A key aspect to the mechanism presented in Figure 8 is its
account of how proton transfer from the oxime group to the
divalent alkenyl carbon results in regioselectivity. While the
acyclic radical cation is highly acidic, the 5-exo cyclic radical
cation intermediate is a very weak acid; for the phenyl
substituted oxime, the calculated pKa is −6.41 for the acyclic
radical cation and +8.23 for the 5-exo radical cation
intermediate (see Table S10). However, the 5-exo neutral
intermediate with the divalent alkenyl carbon oriented toward
the oxime group was not a stable minimum energy geometry;
upon optimization, the oxime proton always transferred to the
divalent alkenyl carbon regardless of the initial orientation of
the N−OH moiety. The final step in the mechanism presented
in Figure 8 is therefore intramolecular proton transfer, which
based on our computational results, is barrierless. Note that
this intramolecular proton transfer necessarily results in only
forming the 5-exo product with the alkenyl proton oriented cis
to the N−O. In contrast, a radical cyclization mechanism
provides no means for a stereoselective protonation; the two
radical 5-exo intermediates are nearly isoenergetic, and hence,
if they were formed, then 5a−5c would be a mixture of cis and
trans isomers, which is inconsistent with the experimental
NMR spectra.
With the mechanistic pathway responsible for the generation
of products 5a−5c described, we now consider alternative
pathways that will compete with the mechanism shown in
Figure 8. As mentioned above, the acyclic radical cation
conformations are highly acidic. As a result, radical cation
cyclization must compete with deprotonation; despite the very
low cyclization barrier and favorable cyclization thermody-
namics, the strong acidity of the radical cations suggests that
deprotonation of the radical cations generated through PET
prior to cyclization is a competitive pathway. Previous research
has shown that iminoxyl radicals can react via several pathways
sometimes leading to complicated reaction mixtures, which is
consistent with our observations in these experiments. For
those radical cations that cyclize into a 5-exo intermediate,
Figure 6 demonstrates that there are two nearly isoenergetic
isomers that will be populated, only one of which can
CONCLUSION
■
In this paper, we discussed our study of the generation of
isoindole N-oxides from the PET-induced cyclization of ortho-
alkynylaryl oximes. This represents the first reported formation
of such compounds as well as demonstrates that the
photooxidative cyclization of 2′-alkynylacetophenone oximes
results in a different product from that in previously reported
metal-catalyzed cyclization reactions. Moreover, the cyclization
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vacuo, the resulting crude mixture was purified using combiflash with
ethyl acetate/hexane as the eluting solvent.
reaction reported in this study is fully stereoselective, with only
a single isomer of the isoindole N-oxides formed.
2-(Phenylethynyl)benzaldehyde.49 2-Bromobenzaldehyde (0.995
g, 5.4 mmol), ethynyl benzene (0.765 g, 7.5 mmol), anhydrous
tetrahydrofuran (10 mL), triphenylphosphine (2.5 mol %), and
triethylamine (1.5 mol equiv) were added to an argon-purged
pressure tube. The mixture was stirred for 10 min, after which
bis(triphenylphosphine)palladium(II) chloride (0.175 g, 5 mol %)
and copper(I) iodide (0.095 g, 9 mol %) were added. The mixture
was heated to 85 ° C and stirred for 24 h. Afterward, the mixture was
diluted with ethyl acetate (15 mL), extracted with water (3 × 30 mL)
and brine (2 × 30 mL), and dried over sodium sulfate. The
concentrated mixture was purified by column chromatography with
ethyl acetate (5%)/hexane (95%) as the eluting solvent to yield the
A detailed computational investigation of the reaction
mechanism revealed that the barrier for 5-exo radical cation
cyclization is very low, less than 3 kcal/mol, allowing radical
cation cyclization to compete with deprotonation. Moreover,
the formation of the 5-exo radical cation intermediate is
thermodynamically favorable by at least −19 kcal/mol. Back-
electron transfer from the DCA radical anion results in a
neutral intermediate, which subsequently undergoes intra-
molecular proton transfer to generate the final product. We
demonstrated that the stereoselectivity of the overall
cyclization reaction originates from the need for the oxime
group and the divalent alkenyl carbon to be oriented toward
each other in the neutral intermediate in order for the
intramolecular proton transfer to occur; all other intermediates
were shown to regenerate the starting material after back-
electron transfer.
1
product as an oil (0.4517 g, 41%). H NMR (400 MHz, CDCl3): δ
10.66 (d, J = 0.8 Hz, 1H), 7.96 (dd, J = 7.8, 0.9 Hz, 1H), 7.65 (ddd, J
= 7.7, 1.3, 0.5 Hz, 1H), 7.61−7.56 (m, 3H), 7.48−7.44 (m, 1H),
7.41−7.38 (m, 3H). 13C NMR (101 MHz, CDCl3): δ 191.89, 136.00,
133.94, 133.38, 131.83, 129.23, 128.77, 128.68, 127.43, 127.04,
122.49, 96.48, 85.03.
1-(2-(2-Phenylethynyl)phenyl)ethenone.49 2-Iodoacetophenone
(0.995 g, 4.0 mmol), ethynyl benzene (0.765 g, 7.5 mmol), and
triethylamine (1.5 mol equiv) were added to an argon-purged
pressure tube. The mixture was stirred for 10 min, after which
bis(triphenylphosphine)palladium(II) chloride (0.175 g, 6 mol %)
and copper(I) iodide (0.095 g, 12 mol %) were added. The mixture
was heated to 50 °C and stirred for 24 h. Afterward, the mixture was
vacuum-filtered with celite, diluted with ethyl acetate (15 mL),
extracted with water (3 × 30 mL) and brine (2 × 30 mL), and dried
over sodium sulfate. The concentrated mixture was purified using a
combiflash with ethyl acetate (10%)/hexane (90%) as the eluting
solvent to yield the product as a yellow oil (0.4517 g, 41%). 1H NMR
(400 MHz, CDCl3): δ 7.76 (dd, J = 7.8, 1.2 Hz, 1H), 7.64 (dd, J =
7.7, 1.0 Hz, 1H), 7.56 (ddt, J = 5.5, 2.7, 1.4 Hz, 2H), 7.48 (td, J = 7.6,
1.5 Hz, 1H), 7.43−7.35 (m, 4H), 2.80 (s, 3H). 13C NMR (101 MHz,
CDCl3): δ 200.56, 140.93, 134.03, 131.67, 131.45, 128.92, 128.84,
128.62, 128.43, 123.04, 121.85, 95.18, 88.62, 30.17.
EXPERIMENTAL SECTION
■
General Information. All chemicals were obtained from
commercial sources and used as supplied without further purification
unless otherwise noted. 9,10-Dicyanoanthracene (DCA) was
recrystallized from pyridine at 80 °C. All aqueous bases were
prepared by dissolving the appropriate amount of solid by mass into a
volumetric flask before being diluted with distilled water and degassed
with heat and agitation under vacuum. All new compounds were
characterized by 1H NMR,13C NMR, and high-resolution mass
1
spectrometry. Known compounds were characterized by H NMR
and 13C NMR and compared to their literature values. NMR spectra
were recorded on a 400 MHz (1H at 400 MHz, 13C at 100 MHz)
1
instrument and obtained with H decoupling. The data are reported
as follows: chemical shift (multiplicity, coupling constant in Hz,
integration). Multiplicities are abbreviated as follows: s = singlet, d =
doublet, t = triplet, q = quartet, quint = quintet, sept = septet, m =
1-(2-(Hex-1-yn-1-yl)phenyl)ethenone.49 2-Iodoacetophenone
(0.902 g, 3.6 mmol), 1-hexyne (0.745 g, 9.0 mmol), and triethylamine
(10 mL, 3.0 mol equiv) were added to an argon-purged pressure tube.
The mixture was stirred for 10 min, after which bis-
(triphenylphosphine)palladium(II) chloride (0.175 g, 7 mol %) and
copper(I) iodide (0.095 g, 14 mol %) were added. The mixture was
heated to 50 °C and stirred for 24 h. Afterward, the mixture was
vacuum-filtered with celite, diluted with ethyl acetate (15 mL),
extracted with water (3 × 30 mL) and brine (2 × 30 mL), and dried
over sodium sulfate. The concentrated mixture was purified by
combiflash with ethyl acetate (10%)/hexane (90%) as the eluting
1
multiplet, and br = broad. All H NMR spectra are reported in δ
(ppm) units and are relative to residual solvent signals of CDCl3 (7.26
ppm) or CD3CN (1.94 ppm). All 13C NMR spectra are reported in δ
(ppm) units and are relative to residual CDCl3 (77.0 ppm) solvent
signals. High-resolution mass spectra were obtained using a Thermo
Scientific Q Exactive Focus benchtop quadrupole Orbitrap high-
resolution mass spectrometer.
Oxidation Potentials. Cyclic voltammetry was used to determine
oxidation potentials of the oxime ethers dissolved in acetonitrile with
tetraethylammonium perchlorate (0.1 M) as the electrolyte. Solutions
were degassed under an argon atmosphere and scanned at a rate of
100 mV/s against a Ag/AgCl reference electrode. The experimental
oxidation potentials were converted into free energies of electron
transfer, ΔGET, using the Rehm−Weller equation, ΔGET = Eox − Ered
− hν.44,45 The Ered of DCA and CA were adjusted by −0.014 V to
correct for the fact that literature reduction potentials were measured
against SCE whereas a Ag/AgCl reference electrode was used in this
study. A +0.044 V correction factor was applied to the measured Eox
to account for the fact that they are peak potentials for an irreversible
system as opposed to the actual oxidation potentials.47,48
General Procedure for the Synthesis of o-Alkynylbenzalde-
hyde and Acetophenones. A 30 mL pressure tube with a screw-
top was evacuated and backfilled with argon prior to the addition of 2-
bromobenzaldehyde or 2-iodoacetophenone (5.0 mmol, 1 equiv),
appropriate alkyne (7.5 mmol, 1.5 equiv), triphenylphosphine (0.12
mmol, 2.5 mol %), and triethylamine (7.5 mmol, 1.5 equiv) in
anhydrous tetrahydrofuran (10 mL). The mixture was allowed to stir
for 10 min, after which bis(triphenylphosphine)palladium(II)
chloride (0.25 mmol, 5.0 mol %) and copper(I) iodide (0.5 mmol,
10 mol %) were added. The mixture was heated in an oil bath and
stirred for 24 h. Afterward, the mixture was diluted with ethyl acetate
and vacuum-filtered using celite. The solution was extracted with
water and brine and dried over sodium sulfate. After concentration in
1
solvent to yield the desired product as an oil (0.3332 g, 33%). H
NMR (400 MHz, CDCl3): δ 7.65 (ddd, J = 7.8, 1.5, 0.5 Hz, 1H), 7.48
(ddd, J = 7.7, 1.4, 0.3 Hz, 1H), 7.39 (td, J = 7.5, 1.5 Hz, 1H), 7.32 (td,
J = 7.6, 1.4 Hz, 1H), 2.72 (s, 3H), 2.46 (t, J = 7.1 Hz, 2H), 1.65−1.58
(m, 2H), 1.53−1.44 (m, 2H), 0.95 (d, J = 14.6 Hz, 3H). 13C NMR
(101 MHz, CDCl3): δ 201.2, 141.2, 134.1, 131.2, 128.4, 127.6, 122.6,
97.0, 79.8, 30.7, 30.2, 22.2, 19.5, 13.7.
1-(2-(3-Methylbut-1-ynyl)phenyl)ethanone. 2-Iodoacetophenone
(0.109 g, 0.44 mmol), 3-methylbutyne (0.052 g, 0.8 mmol), and
triethylamine (5 mL) were added to an argon-purged pressure tube.
The mixture was stirred for 10 min, after which bis-
(triphenylphosphine)palladium(II) chloride (0.017 g, 6 mol %) and
copper(I) iodide (0.009 g, 11 mol %) were added. The mixture was
heated to 50 °C and stirred for 24 h. Afterward, the mixture was
vacuum-filtered with celite, diluted with ethyl acetate (15 mL),
extracted with water (3 × 30 mL) and brine (2 × 30 mL), and dried
over sodium sulfate. The concentrated mixture was purified by
combiflash with ethyl acetate (10%)/hexane (90%) as the eluting
solvent to yield the product as an oil (0.0623 g, 67%).
1H NMR (400 MHz, CDCl3): δ 7.66 (ddd, J = 7.8, 1.5, 0.5 Hz,
1H), 7.47 (ddd, J = 7.7, 1.4, 0.4 Hz, 1H), 7.39 (td, J = 7.5, 1.5 Hz,
1H), 7.32 (td, J = 7.6, 1.4 Hz, 1H), 2.83 (7, J = 6.9 Hz, 1H), 2.73 (s,
K
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3H), 1.28 (d, J = 6.9 Hz, 6H). 13C NMR (101 MHz, CDCl3): δ 201.3,
141.2, 134.0, 131.2, 128.4, 127.7, 122.5, 102.1, 79.2, 30.3, 22.7, 21.6.
HRMS (CI): m/z calculated for C13H15O [M + H], 187.1117; found,
187.1118.
amine hydrochloride (0.6025 g, 2 mol equiv) and pyridine (280 μL,
0.8 mol equiv) were stirred in methanol (22 mL) for 2 h. After
workup, the mixture was purified by combiflash using an ethyl acetate
(35%)/hexane (65%) mixture as the eluting solvent to yield the
desired product as an off-white solid (0.9041 g, 88%). 1H NMR (400
MHz, CDCl3): δ 9.40 (s, 1H, br), 7.61−7.59 (m, 1H), 7.53−7.50 (m,
2H), 7.43−7.31 (m, 6H), 2.40 (s, 3H). 13C NMR (101 MHz,
CDCl3): δ 157.6, 140.0, 133.2, 131.7, 128.70, 128.57, 128.53, 128.47,
128.41, 123.3, 121.8, 93.8, 88.2, 15.6.
Synthesis of o-Arylalkynylbenzaldehyde and Acetophe-
none O-Methyl Oximes. A 40 mL vial fitted with screw-top septa
and equipped with a stirring magnet was charged with the aldehyde (1
equiv), methoxylamine hydrochloride (CH3ONH2·HCl, 98%, 2
equiv), and solid sodium acetate (NaOAc, 4.5 equiv) or sodium
hydroxide (NaOH, 4.5 equiv) before dissolution in 20 mL of 50%
ethanol in water. The mixture was stirred and heated at 85 °C.
Reaction progress was monitored by TLC, and the heating was ceased
once conversion to the product occurred. The mixture was cooled to
room temperature and extracted with dichloromethane (DCM) (3 ×
20 mL). The solvent was removed by concentrating in vacuo, and the
crude product was dried under vacuum. In some cases, products were
purified by dry column chromatography (ether/hexane). Products
were characterized by gas chromatography mass spectrometry (GC−
(E)-1-(2-(Hex-1-yn-1-yl)phenyl)ethanone Oxime (4b).33 1-(2-
(Hex-1-yn-1-yl)phenyl)ethanone (0.300 g, 1.5 mmol), hydroxylamine
hydrochloride (0.1570 g, 1.5 mol equiv), and sodium acetate (0.1344
g, 1.1 mol equiv) were stirred in methanol (20 mL) for 24 h. After
workup, the mixture was purified by column chromatography to yield
1
the desired product as an off-white solid (0.254 g, 85%). H NMR
(400 MHz, CDCl3): δ 8.15 (s, 1H), 7.46−7.41 (m, 1H), 7.33−7.26
(m, 3H), 2.41 (t, J = 7.0 Hz, 2H), 2.32 (s, 3H), 1.62−1.55 (m, 2H),
1.51−1.42 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz,
CDCl3): δ 158.5, 140.0, 133.2, 128.6, 128.3, 127.7, 122.7, 95.3, 79.2,
30.8, 22.2, 19.4, 15.5, 13.8.
MS) and nuclear magnetic resonance spectroscopy (1H NMR and 13
NMR).
C
(E)-2-(Phenylethynyl)benzaldehyde O-Methyl Oxime (1).34 2-
(Phenylethynyl)benzaldehyde (0.4113 g, 2.0 mmol, and 1 mol equiv),
methoxylamine hydrochloride (249 μL, 1.6 mol equiv), and pyridine
(264 μL, 2 mol equiv) were stirred in ethanol (8.2 mL) for 2 h. The
solvent was removed in vacuo, and the residue was diluted with ethyl
acetate (15 mL), extracted with deionized water (2 × 15 mL) and
brine (2 × 15 mL), and dried over sodium sulfate. The concentrated
mixture was purified by combiflash using ethyl acetate (10%)/hexane
(90%) as the eluting solvent to yield the desired product as a yellow
(E)-1-(2-(3-Methylbut-1-yn-1-yl)phenyl)ethanone Oxime (4c). 1-
(2-(3-Methylbut-1-ynyl)phenyl)ethanone (0.5635 g, 2.97 mmol),
hydroxylamine hydrochloride (0.4132 g, 2 mol equiv), and pyridine
(478 μL, 2 mol equiv) were stirred in methanol (15 mL) for 2 h. After
workup, the mixture was purified by combiflash using an ethyl acetate
(35%)/hexane (65%) mixture as the eluting solvent to yield the
desired product as an off-white solid (0.4888 g, 80%). 1H NMR (400
MHz, CDCl3): δ 8.46 (s, 1H), 7.45−7.41 (m, 1H), 7.33−7.30 (m,
1H), 7.29−7.26 (m, 2H), 2.78 (7, J = 6.9 Hz, 1H), 2.33 (s, 3H), 1.25
(d, J = 6.9 Hz, 6H). 13C NMR (101 MHz, CDCl3): δ 158.1, 140.0,
133.1, 128.5, 128.3, 127.7, 122.6, 100.5, 78.5, 22.9, 21.4, 15.5. HRMS
(CI): m/z calculated for C13H16NO [M + H], 202.1226; found,
202.1226.
1
oil (0.2578 g, 67%). H NMR (400 MHz, CDCl3): δ 8.66 (s, 1H),
7.95−7.90 (m, 1H), 7.57−7.52 (m, 3H), 7.38−7.32 (m, 5H), 4.01 (s,
3H). 13C NMR (101 MHz, CDCl3): δ 147.43, 133.35, 132.64, 131.74,
129.58, 128.78, 128.65, 128.55, 125.37, 123.14, 122.97, 94.96, 86.42,
62.30.
Photolysis of o-Arylalkynyloximes with DCA in Acetonitrile-
d3. A nuclear magnetic resonance (NMR) tube was charged with
9,10-dicyanoanthracene (DCA) (5 μM), the oxime or oxime ether
(15 μM), and 1 mL of acetonitrile-d3 (CD3CN). The samples were
photolyzed at 420 nm using a photoreactor equipped with 10 mercury
vapor lamps for a total of 4 h, unless otherwise noted. NMR analysis
was performed every hour. For quantification, an internal standard of
either 4-nitrobenzyl-bromide or 4-nitrobenzaldehyde was added
following photolysis to determine product yield by 1H NMR. Product
isolation conditions: Once removed from the photoreactor, the
contents of multiple (5−20) NMR tubes were combined, and residual
DCA was removed by vacuum filtration. The solvent was evaporated
in vacuo, and the residue was purified by flash chromatography using
dichloromethane and acetonitrile to yield the pure product that was
characterized by NMR.
(E)-1-(2-(Phenylethynyl)phenyl)ethanone O-Methyl Oxime (3).50
1-(2-(2-Phenylethynyl)phenyl)ethanone (0.5965 g, 2.7 mmol, and 1
mol equiv), methoxylamine hydrochloride (410 μL, 2 mol equiv), and
pyridine (435 μL, 2 mol equiv) were stirred in ethanol (10 mL) for 2
h. The solvent was removed in vacuo, and the residue was diluted with
ethyl acetate (15 mL), extracted with deionized water (2 × 15 mL)
and brine (2 × 15 mL), and dried over sodium sulfate. The
concentrated mixture was purified by combiflash using ethyl acetate
(20%)/hexane (80%) as the eluting solvent to yield the desired
product as a yellow oil (0.4950 g, 73%). 1H NMR (400 MHz,
CDCl3): δ 7.59−7.55 (m, 1H), 7.52−7.49 (m, 2H), 7.42−7.40 (m,
1H), 7.37−7.33 (m, 5H), 4.01 (s, 3H), 2.36 (s, 3H).13C NMR (101
MHz, CDCl3): δ 156.95, 140.16, 133.11, 131.57, 128.59, 128.57,
128.53, 123.38, 121.84, 118.08, 116.95, 93.74, 88.30, 62.07, 16.18.
Synthesis of o-Arylalkynylacetophenone Oximes. To a
stirring solution of o-arylalkynyl acetophenone (2.3 mmol, 1 equiv)
in ethanol (20 mL), hydroxylamine hydrochloride (1.5 equiv) and
pyridine (2 equiv) were added. The reaction was stirred at room
temperature for 2 h and then concentrated in vacuo. Afterward, the
residue was diluted with ethyl acetate, extracted with water, and dried
over sodium sulfate. The dried organic layer was concentrated in
vacuo and purified with combiflash by using an ethyl acetate/hexane
mixture as the eluting solvent.
1
(E)-1-Benzylidene-3-methyl-1H-isoindole 2-oxide (5a). H NMR
(400 MHz, CDCl3): δ 8.14 (s, 1H), 7.64−7.60 (m, 3H), 7.51−7.45
(m, 3H), 7.35−7.28 (m, 2H), 7.17 (td, J = 7.4, 1.4 Hz, 1H), 2.48 (s,
3H). 13C NMR (101 MHz, CDCl3): δ 142.79, 141.38, 134.87, 133.02,
129.84, 129.70, 128.92, 128.85, 128.16, 126.71, 121.83, 119.22, 9.76.
HRMS (CI): m/z calculated for C16H14NO [M + H], 236.1070;
found, 236.1069.
(E)-3-Methyl-1-(2-methylpropylidene)-1H-isoindole 2-Oxide (5c).
1H NMR (400 MHz, CDCl3): δ 7.63−7.61 (m, 1H), 7.35−7.28 (m,
(E)-2-(Phenylethynyl)benzaldehyde Oxime (2).30 2-
(Phenylethynyl)benzaldehyde (0.4376 g, 2.1 mmol, and 1 mol
equiv), hydroxylamine hydrochloride (0.2427 g, 1.6 mol equiv) and
pyridine (280 μL, 1.3 mol equiv) were stirred in ethanol (8.7 mL) for
2 h. After workup, the mixture was purified by combiflash using an
ethyl acetate (35%)/hexane (65%) mixture as the eluting solvent to
3H), 7.06 (d, J = 10.6 Hz, 1H), 3.41−3.28 (m, 1H), 2.41 (s, 3H),
1.25 (d, J = 6.7 Hz, 6H). 13C NMR (101 MHz, CDCl3): δ 142.23,
139.84, 138.32, 134.35, 128.84, 128.15, 127.26, 122.11, 119.19, 27.10,
22.40, 9.53. HRMS (CI): m/z calculated for C13H15NO [M + H],
202.1226; found, 202.1227.
Ag(I)-Catalyzed Oxidative Cyclization Reactions of o-
Arylalkynyloximes. A round-bottom flask was charged with the
oxime (0.27 mmol), dichloromethane (2 mL), and silver triflate (2.7
mmol). The sample was stirred for 40 min, and the reaction was
followed by TLC. The solvent was removed in vacuo, and the residue
was purified by column chromatography using a DCM−methanol
gradient. Removal of the solvent yielded the solid product, which was
1
yield the desired product as a white solid (0.3009 g, 78%). H NMR
(400 MHz, CDCl3): δ 8.77 (s, 1H), 8.66 (s, 1H), 7.90−7.87 (m, 1H),
7.59−7.55 (m, 3H), 7.40−7.33 (m, 5H). 13C NMR (101 MHz,
CDCl3): δ 149.21, 133.04, 132.73, 131.74, 129.84, 128.83, 128.72,
128.55, 125.32, 123.33, 122.85, 95.17, 86.30.
(E)-1-(2-(Phenylethynyl)phenyl)ethanone Oxime (4a).33 1-(2-(2-
Phenylethynyl)phenyl)ethanone (0.9521 g, 4.33 mmol), hydroxyl-
1
analyzed by H NMR.
L
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1-Methyl-3-phenylisoquinoline 2-Oxide (6a).33 1H NMR (400
MHz, CDCl3): δ 7.96 (dd, J = 8.6, 0.8 Hz, 1H), 7.79−7.77 (m, 3H),
7.68 (s, 1H), 7.63 (ddd, J = 8.4, 7.0, 1.4 Hz, 1H), 7.56 (ddd, J = 8.0,
7.0, 1.1 Hz, 1H), 7.52−7.45 (m, 3H), 2.95 (s, 3H).
ΔG = ΔGgas(ROH·+) − ΔGgas(CH3COOH) + ΔGsolv(RO·)
+ ΔGsolv(CH3COOH) − ΔGsolv(ROH·+)
− ΔGsolv(CH3COO−)
3-Butyl-1-methylisoquinoline 2-Oxide (6b).33 1H NMR (400
MHz, CDCl3): δ 7.91 (dd, J = 8.7, 0.8 Hz, 1H), 7.71 (dd, J = 7.2, 2.0
Hz, 1H), 7.58−7.50 (m, 2H), 7.48 (s, 1H), 3.06 (t, J = 7.7 Hz, 2H),
2.91 (s, 3H), 1.83−1.76 (m, 2H), 1.50 (dq, J = 14.9, 7.4 Hz, 2H),
1.00 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 149.2,
145.6, 128.7, 128.0, 127.9, 127.6, 126.9, 123.9, 119.9, 30.9, 29.2, 22.8,
14.1, 13.6.
Here, ΔGgas(ROH·+) is the gas phase free energy of the reaction
ROH·+ → RO · + H+ calculated at the m06-2X/6-311++G(d,p) level
of theory with a (99,590) grid. The gas phase free energy of the
proton is −6.28 kcal/mol. The solvation free energy, ΔGsolv(ROH·+),
was calculated using the SM12 solvation model with ChElPG charges
and parameters for acetonitrile;64 the same m06-2X/6-311++G(d,p)
level of theory with a (99,590) grid was used for these calculations. In
the above analysis, acetic acid is used as a reference acid, and we use
the literature value for pKa(CH3COOH) in acetaldehyde, 23.51.65
COMPUTATIONAL METHODS
■
Calculation of the 1H and 13C NMR chemical shifts began by
obtaining optimized geometries in the gas phase using DFT at the
B3LYP/6-31+G(d,p) level of theory with a pruned (99,590) grid.
NMR isotropic shielding tensors were calculated at these optimized
geometries using the gauge including atomic orbital (GIAO) method
with solvent effects included through an integral equation formalism
polarizable continuum model (IEF-PCM) parameterized for chloro-
form with the cavity constructed using UFF atomic radii.51−53 The
NMR isotropic shielding tensors for 1H were calculated at the
mPW1PW91/6-311+G(2d,p) level of theory, whereas these calcu-
lations were performed at the B3LYP/6-311+G(2d,p) level of theory
for 13C. A pruned (99,590) grid was used for all of these calculations.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02318.
■
sı
Comparison of the 1H NMR spectra of 5a−5c and 6a−
6c, detailed comparison of experimental and computa-
tional NMR chemical shifts of 6a−6c and 5b−5c, spin
densities of the 4a−4c radical cations, calculated pKa
values for 3 and 4a−4c radical cations as well as their 5-
exo radical cation intermediates, radical and radical
cation cyclization reaction coordinate diagrams for 3 and
4b−4c, NBO analysis of the radical and the radical
cation forms of 4a−4c, neutral reaction coordinate
diagrams for the ring opening reactions of the 5-exo
trans and 6-endo intermediates of 4a−4c, and radical
cation and neutral reaction coordinate diagrams for 2
(PDF)
1
For 5b, where the experimental H NMR spectrum was measured in
acetonitrile, the NMR isotropic shielding tensors for 1H were
calculated at the WP04/aug-cc-pvdz level of theory with the IEF-
PCM parameterized for acetonitrile. Finally, the calculated NMR
isotropic shielding tensors were converted into NMR chemical shifts
using the calibration curves developed by Pierens.42 These
calculations were performed using Gaussian 09.54
Calculation of the neutral, radical, and radical cation stationary
points followed the same computational procedure as our previous
study of the 2′-arylbenzaldehyde oxime ethers.43 Specifically, we
began with gas phase geometry optimizations performed at the
ωB97X-D/cc-pVDZ level of theory with an (99,590) integration
grid.55,56 An unrestricted formalism was used for the radicals and
radical cations. Vibrational frequency analysis at the stationary points
showed that all minima had no imaginary frequencies, whereas all
transition states only had a single imaginary frequency with a
vibrational motion consistent with the expected reaction coordinate.
Single-point calculations were performed at the optimized geometries
using the ωB97M-V/def2-QZVPP level of theory with a (99,590) grid
for the local exchange-correlation and an SG-1 grid for the nonlocal
correlation.57,58 These single-point calculations included solvent
effects through an IEF-PCM parameterized for acetonitrile with the
cavity constructed using Bondi radii and switching Gaussian surface
charges.51,59,60 The single-point calculations were performed in the
restricted open-shell formalism for the radicals and radical cations.
The single-point electronic energies were combined with the
harmonic enthalpy and entropy to calculate the free energy at T =
298.15 K. All of these calculations were performed using the Q-Chem
5.1 package.61
Experimental NMR spectra for all new compounds as
well as HRMS data, raw thermodynamic information
along with the geometries of all molecular conformations
considered in this study (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Andrew S. Petit − Department of Chemistry and Biochemistry,
California State University, Fullerton, California 92834-
6866, United States; orcid.org/0000-0002-9428-3499;
Email: apetit@fullerton.edu
H. J. Peter de Lijser − Department of Chemistry and
Biochemistry, California State University, Fullerton,
California 92834-6866, United States; Email: pdelijser@
fullerton.edu
Authors
Wan Shin Kim − Department of Chemistry and Biochemistry,
California State University, Fullerton, California 92834-
6866, United States
Victor M. Espinoza Castro − Department of Chemistry and
Biochemistry, California State University, Fullerton,
California 92834-6866, United States
Amanda Abiad − Department of Chemistry and Biochemistry,
California State University, Fullerton, California 92834-
6866, United States
Michael Ko − Department of Chemistry and Biochemistry,
California State University, Fullerton, California 92834-
6866, United States
The ionization potentials were calculated as the difference in the
electronic energy of the radical cation and the neutral states at the
neutral optimized geometries. The ionization potentials were
thermally averaged over all relevant neutral molecular conformations
using the Boltzmann distributions. This thermal averaging included
conformations with the oxime group oriented toward and away from
the alkynyl group.
The pKa of the oxime radical cations, ROH·+, were estimated using
the equation
ΔG
2.303RT
pK (ROH·+) = pK (CH3COOH) +
a
a
Ashley Council − Department of Chemistry and Biochemistry,
California State University, Fullerton, California 92834-
6866, United States
where62,63
M
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Article
(7) Venhuis, B. J.; Dijkstra, D.; Wustrow, D.; Meltzer, L. T.; Wise, L.
Anh Nguyen − Department of Chemistry and Biochemistry,
California State University, Fullerton, California 92834-
6866, United States
Laura Marsalla − Department of Chemistry and Biochemistry,
California State University, Fullerton, California 92834-
6866, United States
Vicky Lee − Department of Chemistry and Biochemistry,
California State University, Fullerton, California 92834-
6866, United States
Thao Tran − Department of Chemistry and Biochemistry,
California State University, Fullerton, California 92834-
6866, United States
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Acknowledgement is made to the donors of the Petroleum
Research Fund, administered by the American Chemical
Society (53793-UR4 and 59497-UNI4). This research was
supported by the National Science Foundation under grant no.
CHE-0844110 and by start-up funds granted by the College of
Natural Sciences and Mathematics at the California State
University, Fullerton. Instrumentation support was provided
by the National Science Foundation MRI (CHE1726903) for
acquisition of a UPLC-MS. This work used the Extreme
Science and Engineering Discovery Environment (XSEDE),
which is supported by the National Science Foundation grant
number ACI-1548562. This work specifically used the Comet
cluster at the San Diego Supercomputer Center through
allocation TG-CHE180057. Additional computational resour-
ces were provided through the Center for Computational and
Applied Mathematics at the California State University,
Fullerton. We thank Ms. Jovy Trejo for her contributions to
the synthesis of some of the compounds and Dr. Paula K.
Hudson for her assistance with the collection and analysis of
the HRMS data.
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