Using experimental and computational approaches to probe an unusual carbon-carbon bond cleavage observed in the synthesis of benzimidazole: N -oxides

Article abstract of DOI:10.1039/d0ob01797c

Experimental and computational studies have been performed in order to investigate an unusual carbon-carbon bond cleavage that occurs in the preparation of certain benzimidazole N-oxides from anilines. The key factor determining the outcome of the reactio

Full text of DOI:10.1039/d0ob01797c

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Leon Sandoval, J. G. Uranga, E. Bujan and N. E. Leadbeater, Org. Biomol. Chem., 2020, DOI:
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DOI: 10.1039/D0OB01797C
ARTICLE
Using experimental and computational approaches to probe an
unusual carbon-carbon bond cleavage observed in the synthesis
of benzimidazole N-oxides
Received 00th January 20xx,
Accepted 00th January 20xx
Fabrizio Politano,a,b Arturo León Sandoval,a Jorge G. Uranga,b Elba I. Bujánb and Nicholas E.
DOI: 10.1039/x0xx00000x
Leadbeater*a
Experimental and computational studies have been performed in order to investigate an unusual carbon-carbon bond
cleavage that occurs in the preparation of certain benzimidazole N-oxides from anilines. The key factor determining the
outcome of the reaction was found to be the substituents on the amine functionality of the aniline.
noteworthy
exceptions.
Thin-layer
chromatography
Introduction
monitoring in these cases showed similar results to all the
others, but 1H-NMR spectroscopic analysis showed an
interesting anomaly. Figure 1(I) shows the typical peak pattern
over the aromatic region of the 1H-NMR spectrum of the
benzimidazole N-oxide products (with -R being aliphatic), and
Figure 1(II) shows the 1H-NMR spectrum of the unexpected
product, with a new signal in the aromatic region (peak d). This
was observed in the reaction of 2-chloro-1,3-dinitrobenzene
(1) with ethanolamine and with ethylenediamine. Instead of
the expected products 4e and 4f, 7-nitro-1H-benzimidazole 3-
oxide (5) was formed (Scheme 2), suggesting that a carbon-
carbon bond cleavage occurs. While the reaction mechanism
for the formation of benzimidazole N-oxides has been broadly
studied,9–11 the only reported carbon-carbon bond cleavage
reported for this class of reaction was due to a decarboxylation
process.7,9 To our knowledge, there have not been any reports
of the cleavage observed in our case. This motivated us to
probe our observation in more detail.
The N-oxide and N-hydroxy derivatives of imidazole and
benzimidazole are interesting families of compounds due their
potential biological activity. They can act as herbicides,
insecticides, and nematicides, as well as possessing
bacteriostatic, anthelmintic, and coccidiostatic properties.1
Benzimidazole N-oxides stand out in particular as they show
broad versatility in catalysis, synthesis, and drug development
for human and veterinary medicine.2 They are potential agents
against tuberculosis, malaria and some neglected tropical
diseases, such as Chagas disease and leishmaniasis.3
The potential application of benzimidazole N-oxides has been
a motivating factor in our research group for the development
of efficient routes for their preparation and we have
developed both batch microwave-heated4 and conventionally-
heated continuous-flow5 protocols (Scheme 1). These
methodologies have several advantages from
a green
chemistry perspective compared with previously-reported
methods.6-8 They comprise of a one-pot two-step process: a
nucleophilic aromatic substitution reaction (SNAr) of different
amines on 2-nitrochlorobenzene derivatives, followed by a
cyclization reaction in basic media. The intermediate is not
isolated; simple precipitation or liquid-liquid extraction is
employed as work-up, and ethanol and water are used as
solvents.
X
X
H2N
R
H
N
Cl
R
microwave
or flow
N
Y
Y
NO2
O
X: -NO2, -CF3
Y: -H, -CF3, -NO2
Using our methodologies, we have prepared a library of over
40 benzimidazole-N-oxides. While most of the desired
compounds were generated as expected, there were a few
Scheme 1 Preparation of benzimidazole N-oxides
Computational chemistry plays a very important role in the
study of reaction mechanisms. The development of new
computational methods, together with advances in
computational power allows for the reduction of calculation
times to a reasonable length.12,13 In this regard, implementing
a computational approach to help us explain the divergent
reaction pathway we observed seemed prudent. However, as in
many other examples in the literature, product selectivity cannot be
a. Department of Chemistry, University of Connecticut, 55 North Eagleville Road,
Storrs, Connecticut 06269, USA. E-mail: nicholas.leadbeater@uconn.edu
b. Instituto de Investigaciones en Físico Química de Córdoba (INFIQC)-CONICET,
Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad
Nacional de Córdoba, Ciudad Universitaria, X5000HUA, Córdoba, Argentina
Electronic Supplementary Information (ESI) available: Experimental and
computational
details,
and
spectral
characterization.
See
DOI:
10.1039/x0xx00000x
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simply reduced to a choice between pathways with different We started our experimental study by revisitViniegw Aortiuclre Otnwlinoe
activation energies.14–16 For instance, competitive reactions that methodologies for the preparation of benzimidazole-N-oxides.
DOI: 10.1039/D0OB01797C
contain the same or similar transition state (TS) could be governed We adapted the reaction of 1 with a series of aliphatic amines
by post-transition-state bifurcation.17 Solutions to these complex (2) that we had initially performed under continuous-flow
chemical problems are the focus of much current research and are conditions, to the “one-pot two-step” batch approach we
resource-intensive. To this end, a simplified approach for the recently reported when using benzylamines as the amine
prediction of reaction selectivity would be highly attractive.
component.4 The reactions were performed employing 1 equiv
Here, we present results of our computational and of 2-chloro-1,3-dinitrobenzene (1) and 2 equiv of the desired
experimental study of the anomalous C-C bond-cleavage amine (2) in 3 mL of ethanol, heating at 120 °C for 20 min.
observed. We bring insight to the reaction mechanism and Following this step, 2 mL of a 0.5 M aqueous solution of K2CO3
establish the structural features that govern the divergent was added, and the heating step repeated. The products
path leading to carbon-carbon bond cleavage.
obtained are shown in Table 1.
Table 1 One-pot two-step approach to the synthesis of benzimidazole-N-oxides.
NO2
H
N
1)
2
(2 equiv.)
Cl
EtOH, 120 ºC, 20min
R
N
2) K2CO3 (0.5 M)
120 ºC, 20 min
4
NO2
O
1
Entry
1
Amine
Products*
2
3
Figure 1 Peak pattern in the aromatic region of the 1H-NMR spectrum of benzimidazole-
N-oxides: (I) typically; (II) in the case of the reaction of 2-chloro-1,3-dinitrobenzene (1)
with ethanolamine and with ethylenediamine.
4
NO2
NO2
H
N
H2N
R
Cl
R
2
*not isolated
5†
6
Ethanol
120ºC
3
NO2
NO2
1
R
: CH2OH
R : CH2NH2
NO2
NO2
K2CO3
H
H
N
OH
NH2
N
7
N
N
NO2
O
H
N
O
4e
4f
8
N
O
5
Scheme
2
Products observed in the reaction of 1 with ethanolamine and
9
ethylenediamine
Results and Discussion
10
Experimental studies
2 | J. Name., 2012, 00, 1-3
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equation formalism variant (IEFPCM) method19 VaienwdArteictlehOannlinoel
(ε=24.852) was used as a continuum solvDeOntI: m10o.1d03e9l./D0OB01797C
We used as our starting point the previously reported
mechanism for the base-mediated cyclization of nitroanilines
to yield benzimidazole N-oxides (Scheme 3).10 The first step
involves the generation of intermediate II from aniline I. The
second step is the reduction of a nitro group to a nitroso
functionality,20,21 followed by the cyclization of the
o-nitrosoimine (III) to give intermediate IV.9,22 A similar
cyclization mechanism has also been reported recently for the
formation of benzoxazoles.23 Intermediate IV bears an sp3
carbon in the nascent imidazole ring, bonded to a hydrogen
and the substituent originating from the parent amine. We
focused attention on this intermediate because we posited
that it was at this stage of the mechanism that the divergence
in pathway would occur; the next step being either C-H bond-
cleavage to give V (Path A) or C-C cleavage giving VI (Path B).
11
*
†
Isolated yields in parentheses. Compounds not isolated – 40:60 mixture of 4e
and 5 was obtained as determined by 1H-NMR spectroscopy.
The reaction of 1 with propylamine (2a) and with butylamine
(2b) led to the expected benzimidazole-N-oxide products, 4a
and 4b, with retention of the alkyl chain (Table 1, entries 1 and
2). The reaction with an amine bearing a longer alkyl chain
(octylamine, 2c) and with an aromatic ring (benzylamine, 2d)
behaved similarly (entries 3 and 4). However, when the
reaction was performed with ethanolamine (2e) and
ethylenediamine (2f), the amines that motivated this study, we
saw the divergence in product outcome that was first
observed in our continuous-flow approach (entries 5 and 6). In
the case of the reaction of 1 with 2e, we observed a 40:60
mixture of the expected product with the alkyl chain intact
(4e) and that with loss of the alkyl chain (5) and, when using
2f, product 5 was formed exclusively.
Upon considering the molecular structures of 2e and 2f, we
posited that they could participate in hydrogen-bonding
interactions and that this could be tied into the mechanism of
alkyl group cleavage. To test this hypothesis, we performed
the reaction of 1 with the corresponding N- and O-methylated
amine analogs, N-methylethylenediamine (2g), N,N-
dimethylethylenediamine (2h), and 2-methoxyethylamine (2i).
With both 2g and 2h, the dealkylated product 5 was formed,
but when using 2i the alkyl group remained intact (entries 7-9).
This suggests that hydrogen-bonding is not a key factor. Next
we considered the distance of the heteroatom with respect to
the nitrogen atom involved in the cyclization reaction, to see if
that may play a role in the dealkylation process. We screened
3-amino-1-propanol (2j, entry 10) and 4-amino-1-butanol (2k,
entry 11) as amine substrates. In each case the product with
retention of the alkyl group was observed. Thus, when the
heteroatom is further away from the benzimidazole ring, the
dealkylation mechanism is not operational, suggesting that a
possible intramolecular process could be occurring.
H
H
R
H
H
CH2R
N
N
N
R
N
O
O2N
N
O2N
NO2
O2N
OH
OH
O
O
I
II
III
H
R
N
H
R
N
N
N
N
N
O2N
O2N
path B
OH
O2N
OH
O
path A
V
IV
VI
Scheme 3 Mechanism for formation of benzimidazole N-oxides highlighting Paths A &
B.
Our objective was to analyse the energy profiles of Paths A and
B for each of the amines used in our allied experimental
studies. With the knowledge that the rate determining step of
the cyclization process occurs prior to fragmentation of
intermediate IV,7,8,10 we assumed that Paths A and B were
directed by thermodynamic factors.
Using intermediate IV as our starting point, we calculated
fragmentation energies for Path A and Path B. In our first pass,
we decided to use a simplified approach for our calculations
that does not take into account the effect of base on the
reaction. For Path A, we modelled unimolecular proton loss
from IV as the fragmentation reaction, and for Path B we
modelled unimolecular C-C bond-cleavage. Our results are
summarized in Table 2 and show the energy values calculated
for C-H and C-C bond-cleavages, taking intermediate IV as the
reference and zero energy. Values shown correspond to the
energy difference between intermediate IV and the
benzimidazole-N-oxide product 4, while the sign indicates if
the processes are endothermic (positive sign) or exothermic
(negative sign). This formalism was used considering that
intermediate IV is expected to be formed independently of the
final product. The selectivity towards C-C or C-H bond cleavage
is posited to be dependent on the kinetic and
thermochemistry of each reaction once IV is generated. For C-
Computational studies
Alongside our experimental work, we carried out a series of
computational studies in order to probe further the origin of
product selectivity in the reaction of 1 with amines. We
performed DFT calculations at the B3LYP/6-31+G* level using
Gaussian 09.18 Each structure was found by a manual
conformational search based on chemical interactions
considering all the possible orientations of the R group. In the
case of the bicarbonate anion, different intermolecular
interactions were considered and the most stable ones were
selected for analysis. Stationary points were characterized as a
minimum in the potential energy surface through normal
mode analysis. Transition states were characterized as first-
order saddle points and their connection with reagent and
product were confirmed through IRC calculations. Solvent
effects were considered in implicit form using the integral
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H bond-cleavage (Path A), there was no notable variation in
energy across the different substrates studied, with the
exception of the case of 6e, the intermediate arising from the
reaction of 1 with ethanolamine (2e) where hydrogen-bonded
stability of the cleavage product is possible (Table 2, entry 5).
For C-C bond-cleavage (Path B) the substituent originating
from the parent amine did play a significant role in the
process. This is not unexpected, given the anticipated unstable
nature of the carbocation intermediate formed in most cases.
To probe this further, we inspected key points of the reaction
coordinate for Path B involving intermediates 6a-6k. The
localization of the positive charge on a primary carbon did
indeed lead generally to energy profiles disfavouring this path;
the energy to break the C-C bond being too high (entries 1-3
and 9-11). As an aside, a rearrangement from a primary to a
secondary carbocation is possible along the reaction
coordinate in the case of the fragmentation products derived
from 6b, 6c, 6j,and 6k (see C-C fragmentation products in SI),
but this is not sufficient to change the outcome of the reaction
from C-H to C-C bond-scission. For 6d, the formation of a
phenyl cation disfavours the C-C bond-fragmentation pathway
even more (entry 4).
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8
9
15.5DOI: 10.1039/D0OB01797C
-4.4
15.6
10.9
15.1
29.9
10
11
21.1
20.6
*The thermochemistry associated with alternative fragmentation pathways (Path
A and Path B) was calculated assuming that the proton generated in the process
subsequently protonates one solvent molecule (ethanol).
When considering the C-C bond-cleavage of intermediates 6e,
6f, and 6g (entries 5-7) both the transition state and product
were found to be significantly stabilized. The transition states
showed a key hydrogen-bonding interaction between the
proton of the heteroatom and the oxygen atom of the
benzimidazole-N-oxide moiety; this reducing the energy
barrier for the C-C bond-cleavage step (Figure 2). Further
analysis showed that scission of the C-C bond occurs in a
concerted fashion with proton transfer between the
heteroatom of the substituent and the oxygen of the
Table 2 Zero-point corrected electronic energies calculated for both C-H and C-C bond-
cleavages from intermediate IV. In each case, the fragment that is cleaved as noted in
the experimental study is highlighted here in red.
Energy (kcal mol-1)*
Entry
1
Intermediate IV
C-H cleavage C-C cleavage
heterocycle core. As
fragmentation are
a
result, the products of the
neutral species: formaldehyde,
methanimine and N-methyl-methanimine, for 6e, 6f, and 6g
respectively (Figure 2a, 2b and 2c). For 6h (entry 8), a
stabilization of the transition state was observed due to the
assistance of the N,N-dimethyl group in the incipient
formation of the carbocation intermediate; positive charge is
shared between the carbon atom and the neighbouring
nitrogen via resonance (Figure 2d).
Our computational study, as well as the experimental results,
show that a heteroatom (N or O) in a β-position to the
nitrogen of the parent amine plays a fundamental role in the
cleavage of the C-C bond in Path B. Bringing together what we
had gleaned thus far, we posited that the C-C bond scission
process could follow at least three different pathways, as shown
16.6
16.6
16.4
11.8
-0.4
62.7
51.2
37.7
85.5
-9.9
-5.2
-7.2
2
3
4
5
6
7
in Figure
3. For substituents with hydrogen-containing
heteroatoms (N or O) in a β-position to the nitrogen of the
parent amine [-OH (6e), -NH2 (6f) -NH(CH3) (6g)], there is the
potential for interaction of these hydrogen atoms with the
negative charge of the N-oxide oxygen atom, leading to
weakening of the C-C bond. This assistance in C-C bond-
cleavage occurs through a six-membered transition state
where bond breaking and proton transfer is a concerted
process (Figure 3, blue pathway). Since this fragmentation
process leads to neutral molecules, this route is energetically
favourable. When the heteroatom is not bound to a hydrogen
atom but instead is an N,N-dimethyl entity (6h), the methyl
groups can contribute to the stability of positive charge on the
nitrogen and contribute to the change in hybridization from
15.8
15.9
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View Article Online
DOI: 10.1039/D0OB01797C
a)
b)
20.0
10.0
0
20.0
10.0
0
+14.6
+5.5
-5.2
-9.9
-10.0
-20.0
-10.0
-20.0
c)
d)
20.0
10.0
20.0
10.0
0
+1.5
+1.3
0
-4.4
-7.2
-10.0
-20.0
-10.0
-20.0
Figure 2 Energy profiles for the reaction with a) ethanolamine, b) ethylenediamine, c) N-methylethylenediamine, and d) N,N-dimethylethylenediamine.
sp3 to sp2 requisite for the formation of the N,N-
dimethylmethyleneammonium cation (Figure 3, purple
C
Z
N
C
C
pathway). This stabilization appears to be very significant as
N
O
Z
N
C
evidenced by the observation that the transition-state barrier
height is the lowest of all the cases studied (Figure 2d).
However, since the fragment generated is cationic, the process
is less favoured than that for 6e, 6f, and 6g. Of note is that this
behaviour is only observed for substrates like 6h, bearing a
tertiary amine moiety, since a similar stabilization is not seen
for 6i which contains a methoxy group. This is likely due to the
higher capacity of nitrogen to share its lone pair electrons with
the vicinal carbon cation as compared to oxygen. As a result,
along with 6a-c and 6j-k, C-C bond-cleavage in 6i follows a
third possible pathway (Figure 3, orange pathway) which is
significantly higher in energy.
Our experimental studies showed that the reaction of 1 with
ethanolamine (2e) afforded both the C-H and C-C cleaved
products (4e and 5). This competition between the two
fragmentation paths is in agreement with the computational
results since Path B for 6e has a higher activation barrier than
that of the other examples studied that showed C-C bond
cleavage. The result is also consistent with the reduced
stabilization of the -CH2OH group of the transition state
geometry compared to -CH2NH2, -CH2NHCH3, and -CH2N(CH3)2
functionalities.
N
O
C
X
N
C
H
N
O
C
Y
N
C
N
O
C
Y
N
C
C
N
O
N
C
C
N
O
X
N
C
N
O
H
Reaction Coordinate
Figure 3 Schematic representation of the three alternative reaction pathways for the
C-C bond-cleavage step from intermediate IV, depending on the nature of the
substituent: 6a-c and 6i-k – orange pathway, 6e-g – blue pathway, 6h – purple
pathway.
Our calculations started with a conformational search since
there are a wide range of possible interactions between the
bicarbonate anion and 6e. The conformational search showed
that the bicarbonate ion had a high affinity for the polar region
of 6e, and the main interactions were identified to be
hydrogen-bonding in nature. The two most stable
conformations differ by only 1 kcal/mol and are in equilibrium
with each other even at room temperature. One of them,
reagent complex A (RC-A), showed a double hydrogen-bond
between the bicarbonate anion and 6e. The hydrogen-bonds
are from the hydrogen of the sp3 hybridized carbon of the
benzimidazole ring and the hydrogen on the CH2OH group of
the parent ethanolamine. The other, reagent complex B (RC-
B), again showed a double hydrogen-bond between the
bicarbonate anion and 6e, this time the oxygen of the N-oxide
moiety and the hydrogen on the CH2OH group of the parent
To probe further the bifurcation observed in the case of 6e, we
performed a series of calculations taking into account the
potential role of the base in the fragmentation process. In the
synthesis of the benzimidazole-N-oxides, potassium carbonate
is employed. A key step in the reaction is the formation of
intermediate II by means of
a deprotonation of the
dinitroaniline precursor; the carbonate base being converted
to bicarbonate. As such, we decided to perform our
calculations using bicarbonate as the base component.
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ethanolamine are involved. The geometries of RC-A and RC-B To probe our hypothesis further, we performed a series of
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as well as the H-bond distances are shown in Figure 4.
experiments designed to detect the forDmOaI:ld10e.h10y3d9e/Dg0eOnBe0r1a79te7Cd
in the reaction of 1 with 2e, predicted from our computational
studies. Given that formaldehyde is both found in and
generated from a range of consumer products, there are a
number of standard analytical methods available for its
detection.25,26 We performed the reaction of 1 with 2e in a
reaction vessel connected to a bubbler going into a water
reservoir, in an approach akin to that use for the analysis of
e-cigarette aerosols.27 Performing the Tollens’ test on the
contents of the water reservoir at the end of the reaction
showed a silver mirror, this being indicative of the presence of
an aldehyde in solution.28 In a second approach, we employed
solid-phase microextraction (SPME). Brady’s reagent,
2,4-dinitrophenylhydrazine (DNPH),29 can be used as a SPME
derivatising agent in order to determine the presence of
carbonyl compounds using chromatographic techniques that
detect the hydrazone formed.30–32 Employing this approach,
and using HPLC-UV as a spectroscopic tool, we detected the
2,4-dinitrophenylhydrazone derivative in the SPME eluted
sample from the reaction of 1 with 2e, this confirming the
generation of formaldehyde. In order to obtain formaldehyde
at a level that was detectable by the techniques we employed,
it was necessary to perform the reaction on a scale ten-times
that of
NO2
NO2
H2
C
N
N
CH2
H
N
N
O
H
O
H
H
O
O
O
O
O
O
O
H
O
H
RC-A
RC-B
0.0 kcal/mol
+1.4 kcal/mol
Figure 4 The geometries of reaction complexes A and B, and more relevant bond
(denoted in black) and hydrogen-bond (denoted in blue) distances. Energy difference
was computed as free energy.
On inspection, the most stable reagent complex (RC-A) has a
geometry closely related to C-H bond-cleavage (Path A), while
RC-B feasibly resembles an intermediate on the path to C-C
fragmentation (Path B) (See Figures S12 and S13 in Supporting
Information). We modelled the energy profiles for Paths A and
B, these being shown in Figure 5a and 5b, respectively. The
activation barriers for both C-H and C-C bond-cleavage are
essentially the same (approximately 6 kcal/mol and -22
kcal/mol, for activation barrier and thermochemistry respectively).
The values obtained have been compared across different DFT
functionals and larger basis sets (see validation of method and basis
set section in the Electronic Supporting Information). All the
methods employed agree that both activation barriers are small; C-
H fragmentation being slightly more favoured. In the case of
thermochemistry C-H fragmentation is also slightly more
exothermic than its C-C bond-scission counterpart. In competitive
reactions such as this where the two products do not have
distinct barriers to formation, analysis is not trivial. Indeed,
development of new algorithms to describe the observed
selectivity is the subject of current research in theoretical
chemistry.17 It is particularly complex in cases were
carbocations and their subsequent rearrangements are
a) C-H fragmentation energy profile Path A
NO2
NO2
N
N
CH2
H
N
N
CH2
H
O
O
H
H
O
O
O
O
O
O
NO2
O
O
N
N
6.0
TS-CH
H
H
CH2
0.0
O
H
O
RC-A
H
O
O
H
O
-22.1
fragmentation products
b) C-C fragmentation energy profile Path B
NO2
H2
C
NO2
H2
C
N
N
O
H
N
N
involved in the mechanism.24 However, in our case
a
O
H
H
H
NO2
O
O
O
qualitative analysis can be undertaken to probe particular
reaction parameters. One such case is the effect of
temperature on the outcome of the reaction. From an
experimental perspective, performing the reaction of 1 with 2e
at 120 °C led to a 40/60 mix of 4e and 5, but reducing the
reaction temperature to 80 °C resulted in an inversion of the
outcome (60% of 4e and 40% of 5). Given that the activation
energies of Path A and Path B are negligible, we propose that
at lower temperature C-H fragmentation is dominant since it is
slightly more exothermic. However, under our reaction
conditions (elevated temperature), formaldehyde generated in
the C-C bond-cleavage process can be released from the
reaction mixture due to its volatility, or it can undergo a
subsequent reaction, these processes driving the reaction
towards C-C bond fragmentation.
O
O
O
H
6.2
N
H
N
O
O
H
TS-CC
0.0
O
O
H
RC-B
O
H
H
O
O
H
-21.0
fragmentation products
c) Geometry of relevant structures
TS-CH
TS-CC
6 | J. Name., 2012, 00, 1-3
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Figure 5 Calculated reaction coordinates for C-H and C-C bond-cleavage observed in the
reaction of 1 with ethanolamine (2e). Energy values denoted in blue correspond to free
energy values expressed in kcal/mol a) Reaction coordinate for Path A; b) reaction
coordinate for Path B; c) Optimized geometries for transitions states for C-H (TS-CH)
and C-C (TS-CC) bond-cleavage.
acknowledged. We thank Dr. James Stuart (University of
Connecticut) for providing SPME cartridges and help us with
HPLC-UV analysis. In addition, we thank Drs. Anthony Provatas
and Adam Graichen (University of Connecticut) for guidance
regarding in chromatography analytical techniques.
View Article Online
DOI: 10.1039/D0OB01797C
which we generally operated. This led us to believe that the
majority of the formaldehyde formed may be undergoing a
Cannizzaro reaction (Scheme 4).28,33,34 The lack of α-H atoms in
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This research was funded in part by the University of
Connecticut Program in Accelerated Therapeutics for
Healthcare. A fellowship to F.P. by the Fulbright Program and
Ministerio de Educación de la Nación Argentina is gratefully
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An unusual carbon-carbon bond-cleavage is explored using a combination of experimental and
computational studies

Organic & Biomolecular Chemistry
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