Copper-mediated reduction of azides under seemingly oxidising conditions: Catalytic and computational studies

Article abstract of DOI:10.1039/c8cy00515j

The reduction of aryl azides in the absence of an obvious reducing agent is reported. Careful catalyst design led to the production of anilines in the presence of water and air. The reaction medium (toluene/water) is crucial for the success of the reaction, as DFT calculations support the formation of benzyl alcohol as the oxidation product. A singular catalytic cycle is presented for this transformation based on four key steps: nitrene formation through nitrogen extrusion, formal oxidative addition of water, C(sp³)-H activation of toluene and reductive elimination.

Full text of DOI:10.1039/c8cy00515j

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Copper-mediated reduction of azides under
seemingly oxidising conditions: catalytic and
Cite this: DOI: 10.1039/c8cy00515j
computational studies†
a
Benjamin Zelenay,ab Maria Besora, b Zaira Monasterio, a David Ventura-Espinosa,
a
Andrew J. P. White, a Feliu Maseras
bc and Silvia Díez-González
*
*
The reduction of aryl azides in the absence of an obvious reducing agent is reported. Careful catalyst de-
sign led to the production of anilines in the presence of water and air. The reaction medium (toluene/wa-
ter) is crucial for the success of the reaction, as DFT calculations support the formation of benzyl alcohol
as the oxidation product. A singular catalytic cycle is presented for this transformation based on four key
steps: nitrene formation through nitrogen extrusion, formal oxidative addition of water, C(sp3)–H activation
of toluene and reductive elimination.
Received 15th March 2018,
Accepted 29th August 2018
DOI: 10.1039/c8cy00515j
rsc.li/catalysis
In this context, several catalytic systems based on copper
have been disclosed in the literature. Copper nanoparticles
Introduction
Amines, primary ones in particular, are essential functional
groups in chemistry, biology and many industries.1,2 Their
importance is inevitably linked to their versatile reactivity
and, in consequence, the use of protecting groups is most of-
ten required in synthetic strategies involving amines. While
carbamates and amides are popular choices, azides offer a
number of advantages as amino protecting groups; they are
easily accessible, soluble, prevent the introduction of addi-
tional steric bulk and, crucially, azides do not react under
many reaction conditions.3
were found active in the hydrogenation of azides with ammo-
nium formate as the H2 source.7 Nevertheless, 0.5 equiv. [Cu]
was required and recycling tests were unsuccessful due to the
air sensitive nature of the catalyst. Reductions of azides into
amines in the presence of a mixture of a copperIJII) salt and a
(super)stoichiometric reductant are also known but barely
general in scope and such a reaction outcome is most often
described as ‘unexpected’ or ‘surprising’.8 It is accepted that
in these examples the azide group is reduced through the oxi-
dation of copperIJI) to copperIJII), which is then reduced by the
The Staudinger reaction is probably the most widespread
methodology for the reduction of azides to amines. Originally
reported in 1919,4 this transformation has notably found
wide application in bioconjugation and functionalisation of
polysaccharides.5 Nevertheless, this reaction requires the use
of stoichiometric amounts of a phosphine or phosphite and
the separation of the resulting oxidised by-products is not al-
ways straightforward.6 The development of catalytic alterna-
tives, particularly if based on readily available and inexpen-
sive metals, would greatly enhance the applicability of and
interest in the use of azides as amino protecting groups.
reducing agent. Otherwise, a stoichiometric amount of
copperIJI) is needed in the absence of an external hydride
source.9 In our opinion, an alternative reported pathway in-
volving the formation of copper–nitrene,10 held better prom-
ise for the development of a robust and more sustainable cat-
alytic system for the reduction of azides to amines. After an
initial test in DMF, the reduction of nitrobenzoxadiazole
azide was reported with 20 mol% of simple copper salts in
degassed aqueous DMSO in the absence of any additional re-
ducing agent (Scheme 1). The isolation of the corresponding
a Department of Chemistry, Imperial College London, Exhibition Road, South
Kensington, SW7 2AZ London, UK. E-mail: s.diez-gonzalez@imperial.ac.uk
b Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of
Science and Technology, Avgda. Països Catalans 16, 43007 Tarragona, Spain.
E-mail: fmaseras@iciq.es
c Departament de Química, Universitat Autònoma de Barcelona, 08193 Bellaterra,
Spain
† Electronic supplementary information (ESI) available. CCDC 1583789–1583791.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c8cy00515j
Scheme 1 Reported reduction of an aryl azide.
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DMSO adduct under such conditions highlighted the non-
innocence of the solvent.11 Even if a single reaction was
reported, the authors remarkably established the intermedi-
acy of triplet copper–nitrene species by EPR and the impor-
tance of water and light in the reaction.
and in the presence of air. No aniline formation was ob-
served after heating for 20 h in THF, EtOAc, MeCN or MeOH,
while moderate conversions were observed in DMSO, toluene,
dioxane and water (Table 1, entries 1–4). Mixtures of these or-
ganic solvents with water were then used with varying results.
While little effect was observed with dioxane, a significant
drop in conversion was obtained with DMSO (Table 1, entries
5 and 7). On the other hand, a promising 30% of aniline 1a
was formed when a toluene/water mixture was used as the re-
action medium (Table 1, entry 6).
Hence, two series of [Cu(DAB)] complexes were screened in
1 : 1 mixtures of toluene/water (Table 2). Cationic homoleptic
complexes systematically outperformed their neutral hetero-
leptic counterparts (Table 2, entries 1–5 vs. 10–13) with the
catalyst bearing DABAnis ligands displaying the highest cata-
lytic activity, up to 54% conversion into 1a (Table 2, entry 4).
In an attempt to improve these results, several [Cu(NHC)]
complexes (NHC = N-heterocyclic carbenes) were also scre-
ened. In this case, neutral [CuX(NHC)]21 catalysts led to bet-
ter conversions to 1a than the related [CuIJNHC)2]X22
complexes. This is probably due to the absence of strong nu-
cleophiles in the reaction mixture capable of activating the
latter.22 In any case, only moderate conversions were
obtained with any of these complexes.
Copper–nitrene derivatives are elusive species;12 neverthe-
less, they are accepted intermediates in catalytic alkane
amination and alkene aziridination reactions.13 Their role in
this aziridination process has been computationally stud-
ied,14 as well as fundamental aspects of the metal–nitrene
bond.15 Some of us also have experience in the computa-
tional study of the role of copper nitrenes in olefin
aziridination,16 transfer to alkynes,17 formation of oxazoles,18
and reaction with hydrocarbons.19 Taking into account the
highly reactive nature of metal nitrenes, we hypothesised that
the use of ligands could be instrumental in their application
in reduction reactions. Herein we report our efforts in devel-
oping a chemoselective copper-based catalytic system for the
reduction of aryl azides to the corresponding anilines in the
absence of an additional reductant as well as our mechanistic
studies to establish the identity of the hydride source.
Results and discussion
Catalytic studies
It is important to note that under these reaction condi-
tions no reduction occurred with simple copper salts such as
[CuIJNCMe)4]BF4, CuI, or CuCl2, which confirms the impor-
tance of the ancillary ligand. It was also observed that the tol-
uene/water ratio had an important impact on the reaction
outcome with some of the catalysts tested. Notably, 84% con-
version (instead of 54%) was obtained with [CuIJDABAnis)2]BF4,
or 55% (instead of 25%) with [CuIIJSIPr)] when the toluene/
water ratio was changed from 1 : 1 to 1 : 2. Such an effect was
not general, though, and it was not observed with other
NHC- or DAB-bearing complexes. No further improvement,
only significant decomposition, was observed with higher wa-
ter ratios.
We started our optimisation studies with the screening of the
[Cu(DAB)] complexes (DAB = diazabutadiene) we recently
reported.20 4-Nitrophenyl azide and [CuIJDABCy)2]BF4 were cho-
sen to test the effect of solvents in a model reaction
(Table 1). All reactions were carried out in technical solvents
Table 1 Solvent screening
Since the best conversions so far had been obtained with
a DAB ligand bearing an unencumbered electron-rich substit-
uent on the nitrogen atoms, we next synthesised several
related copperIJI) complexes. Three diimine ligands bearing
dimethylamino (DMA) or trimethoxy (3MeO) aryl substituents
were reacted with [CuIJNCMe)4]BF4 at room temperature to ob-
tain the corresponding homoleptic complexes 2–4. These
were isolated in good to excellent yields after a simple recrys-
tallization (Scheme 2). Alternatively, similar complexes bear-
ing iminopyridine (ImPy) ligands were also prepared follow-
ing reported procedures (5 and 6).23 The steric bulk of the
iminopyridines is significantly smaller than that of the corre-
sponding diazabutadienes, and therefore, two related com-
plexes 7 and 8 with larger adamantyl or diisopropylphenyl
groups were also synthesised for comparison.
Entry
Solvent
Conva [%]
1
2
3
4
5
6
7
DMSO
Toluene
Dioxane
Water
DMSO/water (1 : 1)
Toluene/water (1 : 1)
Dioxane/water (1 : 1)
28b
14
10
19
19c
30
16
Complex 2 could be handled in air but it decomposed af-
ter a few days even when kept under a nitrogen atmosphere.
All other complexes were indefinitely stable towards oxygen
and moisture. All complexes were fully characterised, as
a 1H NMR conversions are the average of two independent reactions
and are calculated with respect to 1,3,5-trimethoxybenzene as the
b
internal standard. 11% of the DMSO adduct also formed; see
c
Scheme 1. No DMSO adduct was observed.
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Table 2 Catalyst screening
Entry
[Cu]
Conva [%]
Entry
[Cu]
Conva [%]
1
2
3
4
5
6
7
8
9
[CuIJDABCy)2]BF4
[CuIJDABAd)2]BF4
[CuIJDABtBu)2]BF4
[CuIJDABAnis)2]BF4
[CuIJDABMes)2]BF4
[CuIJIPr)2]PF6
[CuIJSIPr)2]PF6
[CuIJSIMes)2]PF6
[CuIJIAd)2]PF6
41
14
5
54
7
16
9
3
10
11
12
13
14
15
16
17
18
[CuClIJDABCy)]
[CuClIJDABAd)]
[CuClIJDABtBu)]
[CuClIJDABAnis)]
[CuIJDABDipp)IJNCMe)2]BF4
[CuI(IPr)]
[CuIIJSIPr)]
[CuClIJSIPr)]
[CuI(IAd)]
22
11
6
32
10
26
25
25
23
19
a 1H NMR conversions are the average of two independent reactions and are calculated with respect to 1,3,5-trimethoxybenzene as the internal standard.
detailed in the ESI.† Spectroscopic data for DAB24 complexes
2–4 and ImPy25 complexes 5–8 were in good agreement with
those of related known complexes.
Suitable crystals for single crystal X-ray diffraction could
be obtained for complexes 3, 7 and 8 by slow diffusion of pe-
troleum ether in DCM solutions (CCDC 1583789, 1583790 &
Scheme 2 Synthesis of copperIJI) complexes.
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Fig. 1 Structure of the two independent cations, 3-A (right) and 3-B (left), present in the crystal of [CuIJDABDMA)2]BF4 3. Most hydrogen atoms are
omitted for clarity.
1583791, respectively). A summary of the crystallographic
data for these compounds is provided in the ESI.† Ball and
stick representations of the obtained structures are given in
Fig. 1–3, and selected bond lengths are provided in the cap-
tions. Despite numerous attempts, the crystal structure of 3
is of poor quality, so only the gross features of the structure
are reliable.26 Despite the evident issues, the structure de-
rived from this data clearly confirms the reported nature of 3
as a [CuIJDABR)2]+ derivative. The structure contains two inde-
pendent copper cations (3-A and 3-B), two independent BF4
anions, and two independent included dichloromethane sol-
vent molecules (Fig. 1). The bond lengths and angles for 3-A
and 3-B can be found in the corresponding CIF file.
the exception of 2, which might be attributed to the instabil-
ity of this copper complex. Gratifyingly, full conversions were
obtained with DAB complexes bearing
a
dimethyl-
aminophenyl substituent (Table 3, entries 3 and 4). Such im-
provement in catalytic activity might be rationalised by the
increased stability of diimine ligands and the corresponding
Complexes 7 and 8 crystallised in the monoclinic (P21/n
¯
space group) and triclinic systems (P1), respectively. As
expected, they both displayed tetracoordinated copper centres
in a distorted tetragonal arrangement, with the two CuN2
coordination planes inclined by 80.07(6)° in 7 and by 77.94(8)°
in 8. The sp2 character of the C–N bond in the chelate rings was
confirmed by the respective bond lengths of 1.275(3) and
1.284(3) Å for 7, and 1.274(3) and 1.272(3) Å for 8.27 Further-
more, no significant interaction between the counterion and
the imine hydrogen or any other atom was evident in either structure.
From the obtained crystallographic data, it could be con-
firmed that the steric pressure imposed by ImPy ligands was
significantly lower than in the DAB family. The percentage
buried volume (%VB)28 for ImPyAd and ImPyDipp was found to
be 39.0 and 41.2% compared to 43.6% for DABAd and 44.5%
Fig.
2 Structure of the cation present in the crystal of
[CuIJImPyAd)2]BF4 7. Most hydrogen atoms are omitted for clarity.
Selected bond lengths (Å) and angles (°): CuIJ1)–NIJ1) 2.077(2), CuIJ1)–
NIJ8) 2.026(2), CuIJ1)–NIJ21) 2.081(2), CuIJ1)–NIJ28) 2.020(2); NIJ1)–CuIJ1)–
NIJ8) 81.25(7), NIJ1)–CuIJ1)–NIJ21) 119.79(8), NIJ1)–CuIJ1)–NIJ28) 119.99(7),
NIJ8)–CuIJ1)–NIJ21) 116.67(7), NIJ8)–CuIJ1)–NIJ28) 142.27(8), NIJ21)–CuIJ1)–
NIJ28) 81.42(7).
for DABDipp 20
.
Next, the newly synthesised complexes were tested in the
model reaction (Table 3). Overall, the tailored [CuIJDABR)]
complexes provided improved conversions into aniline with
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lysts.30 Taking into account these results, catalyst 3 was cho-
sen to investigate the reaction scope since both the ligand
preparation and copper complexation steps were higher yield-
ing than those for the preparation of 4.
The reaction scope was then investigated using 10 mol%
of 3 with different aryl azides (Scheme 3). Complete conver-
sions were actually observed with loadings as low as 1 mol%
with 4-nitrophenyl azide.30 However, this is a highly activated
substrate and a higher copper loading was used in all cases
in an attempt to avoid undesirable thermal decomposition of
the starting azides. It is important to note that in the absence
of the copper catalyst no formation of the corresponding ani-
lines was observed, only the expected degradation of the
starting azides in different degrees depending on their
thermal stability.31
All reactions were completely chemoselective and no other
functional groups were affected by the catalytic system. Nota-
bly, tosyl azide and heteroaromatic azides were suitable sub-
strates for this system. In addition, despite the conditions
used, we never observed the formation of aromatic azo com-
pound (or diaryl hydrazine) issue of oxidative dehydro-
genative coupling of the newly formed anilines.32 Unfortu-
nately, no anilines could be accessed from electron-rich
substrates such as 4-methoxyphenyl azide, which was recov-
ered unreacted, as well as alkyl azide such as adamantyl
azide.
Fig.
3 Structure of the cation present in the crystal of
[CuIJImPyDipp)2]BF4 8. Most hydrogen atoms are omitted for clarity.
Selected bond lengths (Å) and angles (°): CuIJ1)–NIJ1) 2.051(2), CuIJ1)–
NIJ8) 2.026(2), CuIJ1)–NIJ21) 2.058(2), CuIJ1)–NIJ28) 2.021(2); NIJ1)–CuIJ1)–
NIJ8) 80.98(9), NIJ1)–CuIJ1)–NIJ21) 110.44(9), NIJ1)–CuIJ1)–NIJ28) 127.33(9),
NIJ8)–CuIJ1)–NIJ21) 134.02(9), NIJ8)–CuIJ1)–NIJ28) 128.58(8), NIJ21)–CuIJ1)–
NIJ28) 80.75(9).
metal complexes when bearing electron-rich substituents on
the nitrogen centre.23a,29 Nevertheless, this beneficial effect
was not apparent when the iminopyridine scaffold was used
instead (Table 3, entries 5 and 6). Indeed, only disappointing
NMR yields in 1a were obtained with these complexes, but
interestingly, the best performing catalyst in this series was
Computational studies
Due to the unusual nature of this transformation and the
lack of an obvious hydride source, we carried out a computa-
tional study of the mechanism of the reaction of [CuIJDABR)]
complexes with aromatic azides. Calculations were conducted
with phenyl azide and [CuIJDABMe)2]+ as the model system
with the BP86-D3 functional and a double-zeta plus polarisa-
tion basis set.26 A collection data set of all computational
data is accessible in the ioChem-BD repository.33 All energies
presented correspond to free energies in solution at 373.15 K
unless stated otherwise.
the one bearing
a bulkier group on the imine arm,
[CuIJImPyDipp)2]OTf.
In order to discriminate the catalytic activity of complexes
3 and 4, lower metal loadings were then tested. Nevertheless,
identical conversions were obtained in all cases for both cata-
Table 3 Second catalyst screening
Prior to the actual mechanistic study, we needed to iden-
tify the oxidised product and reducing agent. No oxidation of
the complex or ligand was observed experimentally, and
therefore, only toluene and/or H2O could act as reductants.
Both toluene and water may undergo different oxidation pro-
cesses, as depicted in Fig. 4. Even if all of them were found
thermodynamically feasible, some could be ruled out for dif-
ferent reasons. The formation of H2O2 under catalytic condi-
tions would result in the oxidation of anilines to their corre-
sponding hydroxylanilines,34 which was never observed in
our reactions. Water splitting leading to the formation of O2
would have been particularly interesting, but preliminary cal-
culations of possible dinuclear intermediates35 led to
unviable energies.26
Entry
[Cu]
Conva [%]
1
2
3
4
5
6
7
8
[CuIJDABAnis)2]BF4
84
25
>95
>95
38
34
22
57
[CuIJDAB3MeO)2]BF4 2
[CuIJDABDMA)2]BF4 3
[CuIJMeDABDMA)2]BF4 4
[CuIJImPyDMA)2]OTf 5
[CuIJImPyAnis)2]OTf 6
[CuIJImPyAd)2]OTf 7
[CuIJImPyDipp)2]OTf 8
Overall, oxidation products from toluene appear more re-
alistic thermodynamically. However, neither benzylic alcohol,
benzaldehyde, nor bibenzyl could be detected at the end of
a 1H NMR conversions are the average of two independent reactions
and are calculated with respect to 1,3,5-trimethoxybenzene as the
internal standard.
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Scheme 3 ijCuIJDABDMA)2]BF4
3
mediated reduction of azides. Isolated yields are the average of two independent experiments.
1H NMR conversions are shown in brackets when complete conversions were not achieved. These are the average of two independent reactions
and are calculated with respect to 1,3,5-trimethoxybenzene as the internal standard.
our catalytic reactions. While bibenzyl was found stable un-
der catalytic conditions, complete decomposition of benzyl
alcohol or benzaldehyde was observed after heating them
overnight in the presence of [CuIJDABDMA)2]BF4 and aniline.
No decomposition products could be identified from these
reactions but an insoluble sludge was recovered, indicative of
significant oligomerisation/polymerisation. In an attempt to
reduce the decomposition of the oxidation product, the
model reaction was carried out at 70 °C. While aniline forma-
tion dropped to 42% at this temperature, the GC-MS analysis
of the organic phase now showed that benzyl alcohol was
present even if it was only a minor product. No alcohol was
detected when the organic phase was concentrated under re-
duced pressure before GC-MS analysis, which confirms how
sensitive benzyl alcohol is even in the presence of traces of
our copper catalyst or its derivatives. Accordingly, the model
reaction for the DFT studies contained benzyl alcohol as the
oxidation product (Scheme 4).
The complete reaction cycle was computed and an over-
view with selected intermediates is shown in Scheme 5 and
their corresponding energies are in Fig. 5. The full reaction
cycle is depicted in the ESI† (Scheme S1).
Starting from [CuIJDABMe)2]+ I.1, one of the DABMe ligands
is displaced by water and aniline to form a tetracoordinated
copper intermediate I.3. Considering the low configurational
stability in solution of these complexes,20 such displacement
is expected to be straightforward when diluted. DABDMA par-
tially hydrolysed under catalytic conditions (hot toluene/water
mixture) forming traces of 4-(dimethylamino)aniline, which
would be enough for the first catalyst turnover to take place.
Methyl amine would be formed from model [CuIJDADMe)2]+,
however, aniline was expected to mimic better the behaviour
of 4-dimethylaminoaniline that is formed experimentally.
Phenyl azide would then coordinate the copperIJI) centre by
displacing the water molecule to give intermediate II, which
Fig. 4 Overview of the energies of different oxidation products. Free
energies at 373.15 K in kcal mol−1
.
Scheme 4 Model reaction for computational studies.
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Scheme 5 Overview of the proposed catalytic cycle with selected intermediates.
is very close in energy to I.3 (Scheme 5). Dinitrogen is then
extruded in TSIJII) with an activation energy of 30.8 kcal mol−1
(Fig. 5). This is a relatively high energy barrier for a reaction
that takes place at 373.15 K, but the irreversibility of this step
contributes to the progress of the reaction. It is noteworthy
that the uncatalysed extrusion of N2 from phenyl azide has
been calculated to proceed through a transition state above
45 kcal mol−1.36 From TSIJII), a singlet nitrene intermediate III
is formed to then undergo a spin-cross over to give the more
stable triplet species of III (Scheme 5). The minimum energy
conversion point (MECP) for the spin-crossover was located
at 2.7 kcal mol−1, close to the singlet species with III at 3.2
kcal mol−1. The MECP has a free energy 0.5 kcal mol−1 below
the singlet; this is due to thermal and entropic contributions
as its potential energy is actually 1.2 kcal mol−1 above.
Next, coordination of a water molecule forms IV, where wa-
ter acts as a proton shuttle to form a diamido intermediate V,
2.5 kcal mol−1 below the triplet III. This water molecule then
undergoes a formal oxidative addition through TSIJV) to form
a copperIJIII) hydroxyl amido aniline complex VI.1. This penta-
coordinated copperIJIII) intermediate can interact with a tolu-
ene molecule through the aromatic ring. However, for the
amido ligand to be able to receive a hydrogen from the bound
toluene, it needs to be in an equatorial position. The conver-
sion from VI.1 to VI.5 shows the required rearrangement to
bring the amido group to an equatorial position and the
Fig. 5 Free energy diagram for the proposed catalytic cycle with selected intermediates at 373.15 K and in kcal mol−1
.
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Scheme 6 Rearrangement sequence to VI.5. Free energies at 373.15 K and in kcal mol−1
.
aniline group to an axial one (Scheme 6). This process is
assisted by an additional water molecule that is present in the
second coordination sphere of the copper centre.
that the presence of the nitro group significantly lowers the
barrier for nitrogen extrusion to 24.1 kcal mol−1. This barrier
is fully consistent with a reaction taking place at 373.15 K
and explains the need for an EWG on the substrate. This pro-
posed mononuclear mechanism is further supported by pre-
liminary kinetic studies to determine the reaction order with
respect to the catalyst. Indeed, 4-cyanophenyl azide was
reacted under optimal conditions with either 5 or 10 mol%
of [CuIJDABDMA)2]BF4, confirming a reaction order of 1 for the
catalyst.26 On the other hand, the intermediacy of species
such as VII and IX.2 can be directly linked with the original
complex screening (see Table 2 and Scheme 5). These inter-
mediates are necessary for the C–H activation and reductive
elimination steps and because of their high coordination
numbers, they are susceptible to be destabilised/unattainable
when bulkier ligands (particularly NHCs) are coordinated to
the copper centre.
Following this rearrangement, toluene binds through
π-interactions to form a copperIJIII) complex VII. Then, an sp3
hydrogen from toluene is transferred to the amido ligand with
a very reasonable activation barrier of 11.3 kcal mol−1. This
transfer seems to be a radical process rather than a deproton-
ation as a Mulliken spin-density of 0.57 was observed on the
nitrogen of the former nitrene before the transfer, decreasing
to 0.34 on TSIJVII) and to 0.11 on VIII in the triplet spin state.
Toluene has no spin-density on the sp3 carbon in complex VII
and the spin-density increases to 0.32 on TSIJVII) and to 0.53
on VIII in the triplet spin state. These values indicate the
movement of the unpaired electron from the nitrogen to car-
bon or in other words, the transfer of a hydrogen radical.
Following this hydrogen abstraction, the triplet copperIJIII)–
benzyl intermediate VIII readily undergoes a spin-crossover
(barrier of 1.1 kcal mol−1) to form a much more stable singlet
species (−17.3 kcal mol−1 compared to −5.5 kcal mol−1,
Scheme 5). Aniline, the model reaction product, is then
displaced by a water molecule without a significant increase
in free energy, after which benzyl alcohol is reductively elimi-
nated and the active catalytic species I.3 is regenerated. As
previously mentioned, benzyl alcohol is unstable under our
catalytic conditions, which explains its absence in the reac-
tion mixtures.
Finally, important similarities can be drawn between our
catalytic system and the one shown in Scheme 1. Both mech-
anisms appear to have triplet nitrenes as key intermediates
and be accelerated by standard room light. Indeed, when the
reduction of 4-nitrophenyl azide was carried out in the dark
1
only 39% of the expected aniline 1a was observed by H NMR
spectroscopy. Nevertheless, significant differences can also
be found: our reactions are insensitive to the presence or ab-
sence of dioxygen and the inclusion of water in the reaction
medium greatly accelerates the reaction.
The reaction mechanism in Scheme 5 and Fig. 5 discussed
above is one of a variety of different possibilities that were com-
putationally explored. Other potentially active species for the
nitrogen extrusion step are reported in the ESI,† as well as an
alternative reaction mechanism without aniline coordination.
Overall, the rate limiting step of this mechanism is the ni-
trogen extrusion to form the reactive nitrene. In the model re-
action, this is associated with a rather high barrier of 30.8
kcal mol−1. We have verified experimentally that phenyl azide
does not react with our system and that the presence of an
EWG on the substrate is key for the reduction to take place.
Calculations using 4-nitrophenyl azide for this key step show
Conclusions
A careful choice of copperIJI) catalyst has led to the develop-
ment of a new protocol for the reduction of azides under very
simple conditions. This reduction was performed in the pres-
ence of air and water; still no undesired oxidation by-
products were formed. Complex 3 is readily available and in-
definitely stable towards air and moisture. This stability, to-
gether with its remarkable activity, was instrumental for the
development of a robust and user-friendly catalytic system.
DFT calculations suggest that the presence of an EWG group
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on the substrate accelerates the rate limiting step and sup-
port the intermediacy of a triplet carbene and the role of tolu-
ene as a hydride source through the abstraction of one of its
sp3 hydrogen atoms. This is in agreement with the experi-
mental lack of reactivity of electron-rich aryl azides, which
were recovered unreacted with no sign of C(sp3)–H activation.
The importance of these results is twofold. First, it repre-
sents a necessary step towards the development of a viable
and general catalytic alternative to the Staudinger reaction.
Secondly, the promise of copper-mediated oxidation of ali-
phatic C–H bonds under such simple conditions is of high
interest.37 Of note, benzyl alcohol is stable in the presence of
anilines in hot toluene/water as well as with catalyst 3 in the
absence of a base. Hence, the observed instability of benzyl
alcohol in these reactions is directly linked to the presence of
equimolar amounts of an aniline in the reaction mixture and
not the copper complex itself. With an improved mechanistic
understanding in hand, we are currently working on broaden-
ing the azide scope of our system through catalyst design. Ef-
forts to isolate a stable oxidation product are also ongoing
since it would not only confirm the proposed mechanism but
also allow its application to challenging C–H activation pro-
cesses. Results will be reported in due course.
empirical dispersion correction of Grimme (BP86-D3).40 The
selected basis set was 6-31G(d) for C, N, O and H,41 and SDD
for Cu with the corresponding electron core potentials.42 The
validity of the description was confirmed by benchmarking
with a variety of functionals, as reported in the ESI.† All geom-
etry optimisations were carried out in water solvent (SMD)
without symmetry restrictions. We confirmed the nature of all
computed stationary points as minima or transition states
through vibrational frequency calculations. Systematic confor-
mation analyses were carried out for all steps and therefore
only results with the most stable conformers are discussed.
Free energy corrections were calculated at 373.15 K and 105
Pa pressure, including zero point energy corrections (ZPE).
Minimum energy crossing points (MECP) were computed with
the program supplied by Harvey.43 The reported MECP free
energies correspond to an average of those for the two inter-
vening states. A collection data set of all computational data
is accessible in the ioChem-BD repository,33 and can be
accessed via https://doi.org/10.19061/iochem-bd-1-97.
BisIJN,N′-bisIJ4-N,N-dimethylaminophenyl)-1,4-diazabuta-1,3-
dien)copperIJI) tetrafluoroborate [CuIJDABDMA)2]BF4 (2)
[CuIJNCMe)4]BF4 (78.9 mg, 0.25 mmol) and DABDMA (159 mg,
0.50 mmol) were suspended in dry, degassed DCM (15 mL)
under a N2 atmosphere and stirred at room temperature for
16 h. The reaction mixture was then filtered through Celite
and concentrated to a volume of ∼5 mL under reduced pres-
sure, followed by the addition of petroleum ether. The
formed precipitate was collected, washed with petroleum
ether, and dried under reduced pressure to give 2 as a light
green solid (145 mg, 79%). Mp: 293 °C. 1H NMR (400 MHz,
CDCl3): δ 8.95 (s, 4H), 7.51 (d, J = 9.0 Hz, 8H), 6.66 (d, J = 9.0
Hz, 8H), 2.92 (s, 24H). 13C{1H} NMR (101 MHz, CDCl3): δ
151.7, 147.3, 135.5, 124.9, 112.8, 40.2. 19F NMR (377 MHz,
CDCl3): δ −148.3 (s). IR: 2857 (C–H st), 2803 (C–H st), 1600,
1554 (C–N asym st), 1515, 1439, 1358 (C–N sym st), 1297,
Experimental section
Experimental details
All chemicals were obtained from commercial sources and
used without further purification. Air and moisture sensitive
manipulations were performed using standard Schlenk line
techniques. Anhydrous solvents were dried by passing them
through columns of molecular sieves in a solvent purification
system. NMR spectra were measured on Bruker AVANCE 400
spectrometers (1H: 400 MHz, 13C: 101 MHz, 19F: 377 MHz) at
20 °C unless stated otherwise. The chemical shifts (δ) are
given in ppm relative to a tetramethylsilane standard or the
residual solvent signal. The multiplicity is given in br, s, d, t,
q, sept, and m for broad, singlet, doublet, triplet, quartet,
septet, and multiplet. Mass spectra (MS) were recorded on a
Micromass AutoSpec Premier, Micromass LCT Premier or a
VG Platform II spectrometer using EI or ESI techniques at the
Mass Spectroscopy Service of Imperial College London. Infra-
red spectra were recorded using a PerkinElmer 100 series FT-
IR spectrometer, equipped with a beam-condensing accessory
(samples were sandwiched between diamond compressor
cells). Melting points (uncorrected) were determined on a
Gallenkamp electrothermal apparatus. Single crystal X-ray
diffraction patterns were collected using Agilent Xcalibur PX
Ultra A and Excalibur 3 E diffractometers, and the structures
were refined using the SHELXTL, and SHELX-2013 program
systems.
1165, 1047 (BF4 ), 945, 812, 635 cm−1. HRMS calcd for
−
C36H44N8Cu: 651.2985, found 651.2984 ([CuIJDABDMA)2]+).
General procedure for the reduction of azides
In a microwave vial, azide (0.5 mmol) and [CuIJDABDMA)2]BF4
3 (37 mg, 10 mol%) were suspended in toluene (0.33 mL)
and water (0.66 mL) and sealed using a crimped cap. This
mixture was heated to 100 °C for 20 h before being cooled
and filtered through Celite and washed with EtOAc. The or-
ganic filtrate was washed with saturated, aqueous Na4EDTA
(3 × 10 mL), dried over Na2SO4, filtered, and concentrated un-
der reduced pressure. The reported yields are isolated yields
and are the average of at least two independent runs.
Computational details
All calculations were carried out with the Gaussian09 pro-
gram package38 using the methods of density functional the-
ory (DFT). The selected functional was BP8639 with the
Conflicts of interest
The authors declare no conflict of interests.
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Acknowledgements
Dinescu, X. Dai, R. M. Palomino, F. W. Heinemann, T. R.
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This research was financially supported by Imperial College
London, the Engineering and Physical Sciences Research
Council (EPSRC) (EP/K030760/1), the CERCA Programme
(Generalitat de Catalunya) and MINECO (grant CTQ2017-
87792-R and Severo Ochoa Excellence Accreditation 2014-2018
SEV-2013-0319). BZ acknowledges SNF for a travel grant (#
PS1SKP2-168439) and DVE thanks MECD for a doctoral fel-
lowship. Lalita Radtanajiravong is sincerely acknowledged for
carrying out some final experiments.
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