Aerobically-initiated C(sp3)-H bond amination through the use of activated azodicarboxylates

Article abstract of DOI:10.1039/d0ob01562h

Significant advancements in C-N bond formation via C-H bond functionalisation have made it a staple in the production of nitrogen-containing compounds in both industry and academia. However, transition metal-free synthesis, particularly in the case of C(sp3)-N formation, has remained a significant challenge to the synthetic community. Herein we report a procedure for α-C(sp3)-H amination of ethereal compounds through use of azodicarboxylates as the nitrogen source and freely-available atmospheric oxygen to access ethereal radical intermediates via aerobic C-H activation. The use of fluorinated alcohols as solvent is observed to greatly increase the efficiency of the reaction and we show experimentally and theoretically the key role of H-bonding between fluorinated alcohols and azodicarboxylates. Calculations of the condensed Fukui functions of a H-bonded fluorinated alcohol-azodicarboxylate complex correlates with a significantly increased susceptibility of azodicarboxylates to undergo reaction with radicals, which informs a number of recent reports in the literature.

Full text of DOI:10.1039/d0ob01562h

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3
Aerobically-initiated C(sp )−H bond amination through the use of
activated azodicarboxylates
a
a
a
a
André Shamsabadi, Antoine Maruani, Nehaal Ahmed and Vijay Chudasama*
Received 00th January 20xx,
Accepted 00th January 20xx
Significant advancements in C−N bond formation via C−H bond functionalisation have made it a staple in the production of
DOI: 10.1039/x0xx00000x
nitrogen-containing compounds in both industry and academia. However, transition metal-free synthesis, particularly in the
3
case of C(sp )−N formation, has remained a significant challenge to the synthetic community. Herein we report a procedure
3
for α-C(sp )−H amination of ethereal compounds through use of azodicarboxylates as the nitrogen source and freely-
available atmospheric oxygen to access ethereal radical intermediates via aerobic C−H activation. The use of fluorinated
alcohols as solvent is observed to greatly increase the efficiency of the reaction and we show experimentally and
theoretically the key role of H-bonding between fluorinated alcohols and azodicarboxylates. Calculations of the condensed
Fukui functions of a H-bonded fluorinated alcohol-azodicarboxylate complex correlates with a significantly increased
susceptibility of azodicarboxylates to undergo reaction with radicals, which informs a number of recent reports in the
literature.
transition metal reagents in the activation of inert
1
3,14
Introduction
C−H bonds.
Despite providing a direct route to C−N bond
formation, the existence of these limitations and the current
quantity of external additives
means that there is a need to develop C−H bond activation
15,16
required for efficient reaction
The drive to develop efficient and direct transformations for the
construction of complex molecules is always at the forefront of
research in synthetic organic chemistry.1 With growing
environmental concerns around energy efficiency and waste
reduction, it is clear that modern organic synthesis must
continue to develop even more powerful methods for the
construction of complex organic frameworks through
methodologies that are more attractive from a green chemistry
1
7
standpoint.
The use of radical intermediates in C−H bond activation
reactions has seen major developments in the past few decades
owing to improvements in indiscriminate C−H bond abstraction
18
2
and reaction regioselectivity.
Radical pathways offer
simplification and dematerialisation. As such, C−H bond
fascinating alternative approaches for connecting molecular
fragments with high step- and atom-economy that are often
complementary to traditional two-electron processes. Ideally,
said radical pathways would be initiated in a green manner
and/or without the need for complex synthetic manipulation
(see above). There has been some work carried out with this
focus by exploiting aerobic C−H activation, especially on
functionalisation reactions have emerged as a favourable route
to introduce functionality and therefore increase complexity of
molecules in single-step chemical transformations. In
3
particular, C−H bond aminations are an extremely desirable
process due to the plethora of nitrogen-containing compounds
4
found in pharmaceuticals. However, there are still many
3
challenges in this area: (i) the amination of C(sp )−H bonds
2
19–21
aldehydic C(sp )−H bonds,
but there has been a lack of a
remains difficult despite significant advancements in the field of
2
5,6
substantive breakthrough in controlling and exploiting aerobic
C(sp )−N formation (e.g. Buchwald-Hartwig amination), (ii)
3
C(sp )−H activation, which is widely considered as more
the overreliance of directing groups, especially in the case of
3
desirable. With this in mind, we noted that the mechanism for
the oxygen-initiated oxidation of ethers has been extensively
C(sp )−H bond activation, resulting in synthetic routes requiring
additional installation and removal steps of the
2
2–24
7,8
studied
and it is widely accepted that interaction of the
protecting/directing group, (iii) the current standard of using
3
3
α-C(sp )−H in ethers with dioxygen results in the generation of
a nucleophilic radical intermediate (Scheme 1). Thus, it should
nitrene insertion reactions as a means for C(sp )−H amination
suffers from suboptimal regioselectivity and requires the use of
specialised reagents such as organic azides9–11 or azoles as the
nitrogen source, and (iv) the prevalent use of toxic/expensive
12
a. Department of Chemistry, University College London, London, UK.
E-mail: v.chudasama@ucl.ac.uk
†
Scheme 1 Aerobically initiated auto-oxidation of ethers generates ethereal radical
species.
Electronic supplementary information (ESI) available: NMR ( H and 13C), IR, LRMS
1
(
ESI) and HRMS (ESI) of all featured compounds. See DOI: 10.1039/x0xx00000x
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be appreciated that the aerobically initiated auto-oxidation of
ethers offers a unique opportunity for the clean and simple
access to ethereal radical species without the use of any metal
reagents or initiator species. Unfortunately, the majority of
research exploring ether auto-oxidation has resulted in
View Article Online
DOI: 10.1039/D0OB01562H
25
methods to suppress the process rather than utilise it as a Scheme 2 Previously reported peroxide-initiated synthesis of adduct 6aa requiring a vast
3
26–28
excess of THF 1a.
means to achieve discriminate C(sp )−H functionalisation.
In modern radical-based C−N bond formation, commercially
available azodicarboxylates are the standout class of 6ab. As previous reports for the reaction between ethers and
compounds used as radical acceptors. Their strong electrophilic azodicarboxylates utilised the ethereal substrate in vast
nature and possession of a vacant bonding orbital renders these excess,34,37 we were motivated to develop a protocol that
species excellent candidates for attack by nucleophilic radicals employed a more desirable quantity of substrate 1a
and this has been extensively observed when utilising acyl An initial reaction, using 5 equivalents of THF 1a at 21 °C, a
stirring rate of 700 rpm and the reaction mixture exposed to air,
Unfortunately, translation of these protocols to C(sp )−N resulted in a trace amount of desired product (2% yield, Table
formation has been a significant challenge and has either , Entry 1). We were pleased to observe that the same reaction
.
2
29–33
radical chemistry for the formation of C(sp )−N bonds.
3
1
required the substrate to be used in vast excess (ca. 90 eq.), conducted with use of 1 mL of HFIP resulted in a four-fold
considered suboptimal for organic synthesis, or required use of increase in yield (8% yield, Table 1, Entry 2). This suggested that
3
4,35
a specialised initiator/polarity reversal catalyst.
We desired use of fluorinated alcohols as solvent for the transformation
a protocol that would substantially increase the efficiency of the could improve the reaction. We observed that when utilising
process; omitting the requirement of any additional additive HFIP, increasing the reaction temperature also had a large
3
whilst utilising molecular oxygen in air to initiate α-C(sp )−H impact on the efficiency of the reaction (Table 1, Entries 2-4); a
activation. In consideration of this, we looked towards the use reaction temperature of 80 °C afforded a 64% yield of desired
of
fluorinated
alcohols
such
as
1,1,1,3,3,3- product 6ab (Table 1, Entry 4). As it is well understood that
hexafluoroisopropanol (HFIP) and 2,2,2-trifluoroethanol (TFE) stirring rate can have a significant effect on the rate of aerobic
3
0
as reaction solvents. These species exhibit higher relative acidity oxidation, we investigated whether modification of the
and substantial H-bond donating ability when compared to stirring rate affected reaction efficiency (Table 1, Entries 5-7).
traditional solvents.3 We postulated that H-bonding of Gratifyingly, we observed that increasing the stirring rate to
fluorinated alcohols to azodicarboxylates would result in a 1050 rpm resulted in a far more desirable yield of 6ab (83%,
decrease in the energy of the LUMO, thus increasing Table 1, Entry 5), whereas decreasing stirring rate resulted in
susceptibility to nucleophilic attack from ethereal radicals and systematic reductions in reaction yield (Table 1, Entries 6-7).
6
resulting in an increased efficiency of reaction.
Table 1 Optimisation of reaction between THF 1a and DIAD 5b.[a]
Herein, we report the appraisal of this idea and demonstrate
the exploitation of the aerobic C−H bond activation of ethers as
a means to achieve site-selective radical generation. The use of
fluorinated alcohols as both the reaction solvent and to
‘
activate’ azodicarboxylates through a H-bonding interaction
results in efficient, regioselective and metal-free amination of
ethereal α-C−H bonds that requires no additional initiator
species, additives or directing groups.
Yield (%)[b]
Entry
T (°C)
Stirring rate (rpm)
HFIP (mL)
1
2
3
4
5
6
7
8
9
21
21
60
80
80
80
80
80
80
80
80
80
80
80
700
700
700
700
1050
350
0
1
1
1
1
1
1
0.5
2
0
2 (5%)
8 (16%)
52 (64%)
64 (77%)
83 (96%)
60 (66%)
54 (58%)
92 (100%)
78 (92%)
55 (59%)
82 (89%)
68 (75%)
0 (1%)
Results and discussion
To the best of our knowledge, the closest related example to
what we wanted to achieve was the pioneering work of Askani
who reported an unexpected reaction of dimethyl
azodicarboxylate 5a and reaction solvent THF 1a under the
0
1050
1050
1050
1050
1050
1050
1050
34
10
action of UV-light to afford adduct species 6aa
.
Askani
[
c]
d]
e]
1
1
0.5
0.5
0.5
0.5
confirmed a radical pathway for the reaction by repeating the
process using benzoyl peroxide in place of UV-light as the radical
initiator (Scheme 2).
We postulated an aerobic protocol could be developed
through the formation of the integral ethereal radical
intermediate by exposure of the reaction mixture to air. Our
investigations began with optimisation of the reaction between
tetrahydrofuran (THF) 1a and commercially available
diisopropyl azodicarboxylate (DIAD) 5b to form desired adduct
[
1
2
1
1
3[
[
f]
4
2 (4%)
[
a] Reaction Conditions: 1a (5 mmol), 5b (1 mmol), air, 48 h. [b] Isolated yield,
conversion of 5b given in parenthesis based on amount recovered. [c] Use of TFE
instead of HFIP. [d] Use of AcOH instead of HFIP. [e] Use of 10 mol% BHT. [f]
Substrates and solvent degassed and reaction conducted under an argon
atmosphere.
2
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DOI: 10.1039/D0OB01562H
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Scheme 3 α-C(sp )−H amination of ethers 1 using azodicarboxylates 5. [a] Gram scale synthesis. [b] 1:1 ratio of diastereomers. [c] Use of TFE as solvent. [d] Neat conditions.
Finally, a decrease in the amount of HFIP solvent to 0.5 mL DIAD adduct 6ab was performed, which provided the desired
resulted in a highly desirable 92% yield of 6aa (Table 1, Entry 8), product in an 81% yield. Use of 6- and 7-membered ring cyclic
whereas increasing the amount of HFIP resulted in a reduction ethers also proved to be compatible under the reaction
in yield to 78%. With an efficient reaction using HFIP in hand, conditions with desired products isolated in good yields (62–
we investigated the effect of alternative solvents on reaction 71%). However, when employing α-substituted cyclic ether
efficiency. Conducting the reaction in the absence of solvent 2-methyltetrahydrofuran, only 20% of the sole regioisomer 6eb
resulted in only 55% yield (Table 1, Entry 10). Substitution of was observed, with
HFIP to alternative fluorinated alcohol TFE resulted in only a azodicarboxylate recovered. This was intriguing as we
small reduction in yield to 82% (Table 1, Entry 11), whilst use of expected appearance of the tetra-substituted regioisomer 6fb
an alternative acidic solvent AcOH (despite displaying stronger and we hypothesised that acid-mediated cleavage of the C−N
a
significant amount reduced
7
,
3
8
acidity, it is an inferior H-bond donor compared to HFIP ) bond in 6fb brought about through the presence of HFIP (pKa =
resulted in a significant decrease in yield of 6ab (68%, Table 1 9.3) led to the formation of . In an attempt to reduce this
,
7
Entry 12). This provided some evidence that the greater the H- pathway, we utilised comparatively less acidic fluorinated
bonding ability of the solvent, the more efficient the reaction. alcohol TFE (pKa = 12.5). Unfortunately, this did not seem to
To confirm the presence of a radical pathway, we conducted the improve the reaction with regards to yield or reducing
reaction of 1a and 5b under our optimised conditions with formation of by-product
0 mol% of radical inhibitor BHT (2,6-di-tert-butyl-4- under neat conditions (without the use of solvent), a 30:70 ratio
methylphenol) and observed minimal conversion of starting of 6eb to 6fb in 68% yield was observed. To provide evidence
material 5b Table 1, Entry 13). Finally, to demonstrate that the that tetra-substituted α-aminated ethers are unstable under
7. When the reaction was conducted
1
(
reaction proceeds via a dioxygen-initiated pathway, the acidic conditions, subjection of this regioisomeric mixture to
optimised reaction of 1a and 5b was conducted under an inert HFIP then led to decomposition of the tetra-substituted 6fb
atmosphere (utilising degassed reagents) resulted in a modest regioisomer When utilising cyclic acetals, it was observed that
2
% yield of 6ab
(
Table 1, Entry 14).
the use of HFIP as the reaction solvent resulted in the formation
, thereby
With optimised conditions in hand, the generality of the of a large amount of reduced-azodicarboxylate
7
procedure was then appraised (Scheme 3). Besides DIAD, all resulting in suboptimal reaction yields (0–21%). We again
azodicarboxylates trialled gave their respective desired hypothesised that this was due to acid-mediated cleavage of the
products in good to excellent yields (72–94% yield), resulting in electron-rich C−N bond. To our delight, use of the less acidic
ether-azodicarboxylate adducts with carbamate esters that fluorinated alcohol TFE, in this case, proved optimal with
could be removed either under basic (methyl-, ethyl- minimal quantities of reduced-azodicarboxylate
carbamate), acidic (isopropyl-carbamate) or hydrogenation full consumption of azodicarboxylate, resulting in far more
benzyl-carbamate) conditions. A gram-scale synthesis of THF- efficient reactions (59–70% yield). Fascinatingly, when utilising
7 observed and
(
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Scheme 4 TEMPO trapping experiment.
1
,3,5-trioxane as the ether substrate and TFE as the reaction
solvent, we observed 62% of product 6ib (i.e. formylation of
azodicarboxylate species). We suspect this is due to 1,3,5-
trioxane being a formaldehyde trimer which is prone to acidic
decomposition. Indeed, we observed that use of HFIP resulted
in only 15% yield of 6ib. We suspect this is due to rapid
decomposition of 1,3,5-trioxane under the action of the more
acidic HFIP prior to significant C−N formation. The scope of
acyclic ethers was then appraised. Disappointingly, diethyl
Figure 1 NMR titration curve of HFIP with DIAD 5b.
1
The binding constant values were calculated from H-NMR
ether did not appear to not undergo any transformation under titration data using Bindfit41,42 for 1:2 (Host:Guest) non-
the reaction conditions. We suspect that this is due to the cooperative binding stoichiometry. The following equation was
comparatively larger bond dissociation energy (BDE) of the α- used for calculating the binding constant from titration
3
-1
C(sp )−H in diethyl ether (ca. 400 KJ·mol ) compared to cyclic experiments via non-linear fitting method (Nelder–Mead):
-
1 39
ethers (i.e. 380-390 KJ·mol ). To provide evidence for this,
2
2
HG1
K G +HG2 K 4 G
 
 
-1
acyclic dibenzyl ether (which exhibits a BDE of 359 KJ·mol ) was
trialled and the reaction proceeded efficiently with a 63% of
desired adduct 6kb observed. Owing to literature describing the
oxygen-induced auto-oxidation of organic sulfides,40 where K is the binding constant and HG
tetrahydrothiophene (sulfur-analogue of THF) was also trialled
 =
2
2
1
+K

G

+K 4

G

=
HG
−
H
.
NMR data points for DIAD fitted well into this model and
-1
in the reaction conditions; this resulted in the isolation of the yielded a binding constant K of 4.4±0.5 M (initial H-bonding
desired product in 49% yield. Finally, we demonstrate the between HFIP and DIAD), indicating a significant interaction.
potential of the reaction procedure with regards to nitrogen-
based heterocycles through the use of N-Boc pyrrolidine HFIP to DIAD 5b, we decided to conduct theoretical studies on
affording an 81% yield of desired adduct 6mb
the nature and effect such an interaction would have on the
Having experimental support for the H-bonding effect of
.
For our initial investigations of the reaction mechanism, a mechanism of the overall chemical transformation. First, we
control experiment using 2,2,6,6-tetramethyl-1-piperidinyloxy were interested in whether DIAD was likely to be accepting a H-
(
TEMPO) as a radical scavenger was conducted under the bond through a nitrogen atom on the N=N bond, or the carbonyl
optimised conditions (Scheme 4). As expected, a complete oxygen on the carboxylate esters adjacent to the N=N bond
retardation of the reaction was observed and the THF-TEMPO
adduct was detected by LC-MS analysis (MS = 228.2 Da), bonded through a carbonyl oxygen atom (denoted as 5b ) and
(
Figure 2). Thus, the energy of DIAD 5b, DIAD-HFIP complex H-
O
suggesting the mechanism proceeds through the initial DIAD-HFIP complex H-bonded through a nitrogen atom
N
formation of a THF radical.
(denoted as 5b ) were calculated.
It is well understood that fluorinated alcohols such as HFIP
The molecules were subjected to geometry optimisation at
and TFE are excellent hydrogen-bond donors and this has been B3LYP/6-311++G(d,p) level; the resulting optimised structure
extensively studied in the interaction with hydrogen-bond are given in Figure 3. Following this, calculations in vacuo were
36
accepting ethers. We proposed that fluorinated alcohols can performed at M06-2X/6-311++G(d,p) level of theory and the
O
N
also participate in efficient H-bonding to azodicarboxylates. We energy difference between 5b and 5b was found to be 1.8
1
-1
N
therefore experimentally examined, through H NMR titration, kcal·mol , 5b being the lowest in energy. The energy
the formation of H-bond complexes of HFIP with DIAD. The difference being relatively small, both complexes were further
titration was conducted through successive additions of DIAD to investigated to understand the role of HFIP in the reaction.
an NMR sample of a fixed quantity of HFIP in CDCl
3
and the
As α-ethereal radicals are nucleophilic in nature they will
change in the chemical shift (δ) of the hydroxyl proton was interact favourably with electrophilic entities such as
O
recorded. A significant downfield shift of the proton was azodicarboxylates; as such, the LUMO energies of 5b and 5b
1
N
observed in the H NMR with increasing quantity of DIAD, and 5b were calculated. They were found to be -2.42 eV for
clearly indicating the formation of a hydrogen-bonded complex DIAD 5b, -2.93 eV for DIAD-HFIP complex 5b and -3.25 eV for
Figure 1). The presence of only one hydroxyl proton signal DIAD-HFIP complex 5b . This suggests that H-bonding to
O
N
(
indicates a fast equilibrium on the NMR timescale.
azodicarboxylates does indeed lower the energy of the LUMO,
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O
condensed Fukui functions for DIAD 5b, DIAD-HFIP
V
c
ie
o
w
m
Ar
p
ticlele
x
O
5
nl
b
ine
DOI: 10.1039/D0OB01562H
and DIAD-HFIP complex 5bN were then calculated, the results
are presented in Table 2
.
These results highlight the impact of H-bonding through the
nitrogen atom where susceptibility of the non-H-bonded
nitrogen N(15) on the N=N bond to radical attack is significantly
increased. By contrast, H-bonding through a carbonyl oxygen
atom did not have a significant effect on the susceptibility of
Figure 2 DIAD 5b, DIAD-HFIP complex H-bonded through a carbonyl oxygen atom 5bO
and DIAD-HFIP complex H-bonded through a nitrogen atom 5bN.
0
Table 2 Condensed Fukui function (f ) values for radical attack on the nitrogen
O
N
atoms on DIAD 5b, DIAD-HFIP complex 5b and DIAD-HFIP complex 5b (HFIP H-
bonded to N(7) on 5b ).
N
5b
5bO
5bN
N(7)
N(15)
0.22
0.21
0.25
0.23
0.11
0.33
Figure 3 (Left) Optimised geometry of 5b, 5bO and 5bN at M06-2X/6-311++G(d,p) level.
(
Right) Corresponding calculated LUMO.
with a significant increase observed upon H-bonding through a
nitrogen atom compared to a carbonyl oxygen atom. The spin
density maps of nitrogen-centred radical intermediates of the
O
N
form
8 following THF radical attack on 5b, 5b and 5b
Scheme 5 Proposed mechanism.
respectively have also been calculated and are presented in
Supporting Information.
DIAD to radical attack. This fits with the theoretically optimised
geometry of azodicarboxylates where the carbonyls of the
carboxylate esters adjacent to the N=N bond are shown to be
practically orthogonal to the N=N bond, indicating that the
molecule is not conjugated and therefore hydrogen-bonding to
the carbonyl oxygen atom should have minimal effect on the
reactivity of azodicarboxylates.
In computational chemistry, Fukui functions are the
reactivity descriptors that enable characterising the relative
susceptibility of sites to electrophilic, nucleophilic and radical
attack and hence are commonly used for the establishment of
the regio- and chemoselectivity observed in reactions. The
condensed Fukui function represent the same underlying idea
but applied to an atom within a molecule rather than a point in
three-dimensional space. The atoms of a molecule, which have
the largest Fukui values, are the most feasible sites for the
attack. For radical attack, the condensed Fukui function of an
atom A is defined as
44
We therefore propose that the mechanism for radical attack
of ethereal radical species
complex 5b proceeds via H-bonding to the adjacent nitrogen
2 on an azodicarboxylate-HFIP
N
on the N=N bond (Scheme 5). The radical adduct species
8 is
then expected to abstract a H-atom from the starting material
1a, forming desired product 6ab and reforming ethereal radical
A
N−1
A
N+1
q
− q
0
f =
A
2
.
2
The described formation of ethereal α-C−N bonds via
aerobic C−H activation represents a fundamental advancement
that allows for the increase in functionality and complexity of
A
N−1
A
N+1
where
q
and
q
are partial charges of atom A in the
molecule with N − 1 electrons and N + 1 electrons, respectively.
Partial charges for both nitrogen atoms were computed using ether substrates in a minimalistic fashion and therefore
atomic dipole moment-corrected Hirshfeld charges.43 The
obviates the need for any undesirable metals, initiators or
additives. The use of atmospheric dioxygen represents a green,
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manuscript represent a fundamentally novel contribution to the
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field of C−H activation.
Conflicts of interest
Scheme 6 Metal-free rupture of the N−N bond in 6ab to form 9.
There are no conflicts to declare.
sustainable and a freely accessible form of oxidant to be utilised
in the synthesis. Furthermore, the formation of the C–N bond
at the α-site in ethers results in the hemiaminal ether skeleton
Acknowledgements
(
HES) and this functionality is commonplace in organic
and bioactive molecules such as Tegafur
chemotherapeutic prodrug) and Crambescin B (voltage-gated
The authors gratefully acknowledge the UCL Graduate School
for funding A.S. and N.A. The authors also acknowledge the UCL
Chemistry Mass Spectrometry Facility (Dr. K. Karu) and the
EPSRC U.K. National MS Facility (Swansea).
4
5
synthesis
(
sodium channel inhibitor) and are also present in a variety of
HIV/AIDS medications (i.e. didanosine, zalcitabine). The formed
ether-azodicarboxylates also offer platforms for further
synthetic manipulation. As an example, access to (protected) α- Notes and references
amino species is highly desirable and we demonstrate the
1
2
R. A. Sheldon, Green Chem., 2008, 10, 359–360.
formation of these structures through cleavage of the N−N
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3
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the amination procedure reported in the study is a powerful
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Conclusions
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In summary, an aerobic approach for α-C(sp )−H amination of
ethereal substrates utilising azodicarboxylates as nitrogen
source has been enabled through the use of fluorinated
alcohols. The use of atmospheric oxygen to generate radical
species and the dual function of fluorinated alcohols as both
solvent and activating agent feeds into the sought-after goal of
simplification and dematerialisation of C−H activation methods.
A broad selection of ether- and acetal-azodicarboxylate adducts
are efficiently prepared by the disclosed methodology. We
provide experimental evidence for the H-bonding interaction
between HFIP and DIAD and explore theoretical studies
suggesting that the H-bonding of HFIP specifically to the
nitrogen atom in DIAD results in a substantial lowering of the
LUMO energy and increases its susceptibility to radical attack.
This finding not only informs the reactions disclosed in this
article but also a number of recent reports in the literature that
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utilise this combination.
We also anticipate that the
interaction we detail between fluorinated alcohols and
azodicarboxylates will provide new opportunities for X−N bond
formations, particularly in radical-based synthesis. Moreover,
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