Porphyrin cobalt(III) "Nitrene radical" reactivity; Hydrogen atom transfer from Ortho-YH substituents to the nitrene moiety of cobalt-bound aryl nitrene intermediates (Y = O, NH)

Article abstract of DOI:10.3390/molecules21020242

In the field of cobalt(II) porphyrin-catalyzed metallo-radical reactions, organic azides have emerged as successful nitrene transfer reagents. In the pursuit of employing ortho-YH substituted (Y = O, NH) aryl azides in Co(II) porphyrin-catalyzed nitrene transfer reactions, unexpected hydrogen atom transfer (HAT) from the OH or NH₂ group in the ortho-position to the nitrene moiety of the key radical-intermediate was observed. This leads to formation of reactive ortho-iminoquinonoid (Y = O) and phenylene diimine (Y = NH) species. These intermediates convert to subsequent products in non-catalyzed reactions, as is typical for these free organic compounds. As such, the observed reactions prevent the anticipated cobalt-mediated catalytic radical-type coupling of the nitrene radical intermediates to alkynes or alkenes. Nonetheless, the observed reactions provide valuable insights into the reactivity of transition metal nitrene-radical intermediates, and give access to ortho-iminoquinonoid and phenylene diimine intermediates from ortho-YH substituted aryl azides in a catalytic manner. The latter can be employed as intermediates in one-pot catalytic transformations. From the ortho-hydroxy aryl azide substrates both phenoxizinones and benzoxazines could be synthesized in high yields. From the ortho-amino aryl azide substrates azabenzene compounds were obtained as the main products. Computational studies support these observations, and reveal that HAT from the neighboring OH and NH₂ moiety to the nitrene radical moiety has a low energy barrier.

Full text of DOI:10.3390/molecules21020242

molecules
Article
Porphyrin Cobalt(III) “Nitrene Radical” Reactivity;
Hydrogen Atom Transfer from Ortho-YH
Substituents to the Nitrene Moiety of Cobalt-Bound
Aryl Nitrene Intermediates (Y = O, NH)
Monalisa Goswami, Christophe Rebreyend and Bas de Bruin *
Van ‘t Hoff Institute for Molecular Sciences, University of Amsterdam, Science Park 904, 1098 XH Amsterdam,
The Netherlands; m.goswami@uva.nl (M.G.); C.Rebreyend@uva.nl (C.R.)
*
Correspondence: b.debruin@uva.nl; Tel.: +31-205-256-495
Academic Editor: Klaus Banert
Received: 16 January 2016; Accepted: 16 February 2016; Published: 20 February 2016
Abstract: In the field of cobalt(II) porphyrin-catalyzed metallo-radical reactions, organic azides have
emerged as successful nitrene transfer reagents. In the pursuit of employing ortho-YH substituted
(
Y = O, NH) aryl azides in Co(II) porphyrin-catalyzed nitrene transfer reactions, unexpected hydrogen
atom transfer (HAT) from the OH or NH group in the ortho-position to the nitrene moiety of the
2
key radical-intermediate was observed. This leads to formation of reactive ortho-iminoquinonoid
(Y = O) and phenylene diimine (Y = NH) species. These intermediates convert to subsequent
products in non-catalyzed reactions, as is typical for these free organic compounds. As such, the
observed reactions prevent the anticipated cobalt-mediated catalytic radical-type coupling of the
nitrene radical intermediates to alkynes or alkenes. Nonetheless, the observed reactions provide
valuable insights into the reactivity of transition metal nitrene-radical intermediates, and give access to
ortho-iminoquinonoid and phenylene diimine intermediates from ortho-YH substituted aryl azides in
a catalytic manner. The latter can be employed as intermediates in one-pot catalytic transformations.
From the ortho-hydroxy aryl azide substrates both phenoxizinones and benzoxazines could be
synthesized in high yields. From the ortho-amino aryl azide substrates azabenzene compounds were
obtained as the main products. Computational studies support these observations, and reveal that
HAT from the neighboring OH and NH moiety to the nitrene radical moiety has a low energy barrier.
2
Keywords: aryl azides; cobalt(II) porphyrins; nitrene radicals; hydrogen atom transfer; azabenzenes;
ortho-iminoquinonoid; phenylene diimine
1
. Introduction
In the context of homogeneously catalyzed organic transformations carbene and nitrene transfer
reactions provide interesting possibilities [1–7]. In these transformations metal catalysts that can
activate carbene or nitrene precursors are employed, typically leading to the formation of metal
carbenoid or nitrenoid species. The thus formed carbenoids and nitrenoids can then add to a variety of
unsaturated bonds in alkenes and alkynes. In addition, metal-catalyzed carbene transfer can be used
in reaction in which carbene moieties formally insert into X
ubiquity of nitrogen atoms in biologically active compounds, it is also interesting to find ways in which
C–N bonds can be formed by addition or insertion of nitrenoids to a C=C or C C bond or into a C–H
bond. Metal-catalyzed nitrene transfer reactions are therefore promising and worth investigating.
Cobalt(II) porpyhrins have proven to be quite successful in this field [ 25]. Besides being
efficient in carbene transfer reactions, cobalt(II) porphyrins have also attracted attention in several
´H bonds (X = O, N, S, Si) [2]. Given the
”
2,8–
Molecules 2016, 21, 242; doi:10.3390/molecules21020242
www.mdpi.com/journal/molecules

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nitrene transfer reactions [11
,14
–16
,
18,21
,22
,26–28]. In the early stages of this type of catalysis it was
quite common to use iminoiodanes or haloamine-T compounds as nitrene sources for transfer to other
molecules [29 33]. These are, however, not the most convenient and benign nitrene sources, as they
–
are poorly soluble and lead to the formation of undesirable side products like phenyl iodide and
other halogen-containing compounds. Organic azides are potentially more interesting nitrene-transfer
reagents [3,5,6], as they are more soluble and the only byproduct formed during the generation of
nitrenes from azides is dinitrogen.
Mechanistically these systems are quite unique as they operate via cobalt(III) nitrene radical
species, formed by electron transfer from cobalt(II) to the nitrene moiety upon activation of the
azide. This leads to discrete radical character of the reactive nitrenoid intermediate. The detailed
mechanistic aspects of two such catalytic nitrene transfer reactions with cobalt porphyrins have
been elucidated by our group previously (Scheme 1) [12
amination of ethylbenzene, toluene, and tetralin (1,2,3,4- tetrahydronaphthalene) was studied with
,
18
,
34
,
35]. The mechanism of C H bond
´
a variety of organic azides like N C(O)OMe, N SO Ph, etc. using density functional theory (DFT) and
3
3
2
electron paramagnetic resonance (EPR) spectroscopy (Scheme 1a) [18]. The mechanism of cobalt(II)
porphyrin-mediated aziridination of styrene with PhSO N was also studied (Scheme 1b) [21]. For both
2
3
amination and aziridination reactions, the DFT calculations revealed a stepwise radical process
involving coordination of the azide to the cobalt(II) center, followed by release of dinitrogen to
produce an unusual “nitrene radical” intermediate
C (Scheme 1). In addition, experimental EPR
spectroscopic studies, combined with DFT EPR property calculations being in good agreement with
III
the experimental data, revealed the formation of a (por)Co
´
N Y nitrene radical adduct C from
‚
the catalyst in the presence of an excess of the azide in benzene. Formation of a nitrene moiety at
cobalt(II)porphyrin effectively leads to electron transfer from the metal to the nitrene, thus reflecting
the redox non-innocence of the nitrene substrate ligand. The spin density of this intermediate resides
almost entirely on the nitrogen atom of the nitrene moiety. More recently, the intermediate
characterized using an array of spectroscopic methods [12].
C was fully
Scheme 1. Mechanisms of cobalt(II) porphyrin catalyzed amination (a) and aziridination (b).

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In order to expand the scope of cobalt(II) porphyrin catalyzed nitrene transfer reactions we
sought to use ortho-substituted aryl azides as substrates, which on activation by Co(II) porphyrins
could undergo subsequent reactions with unsaturated bonds. The idea was in part inspired by our
work on related ortho-hydroxyaryl carbene radicals [20]. Activation of the carbene precursor and
subsequent reaction of the thus generated cobalt(III) carbene radical with phenyl acetylene allowed us
to synthesize 2H-chromenes in good yields (Scheme 2a). The mechanism of this reaction is particularly
interesting, and DFT calculations reveal the formation of the salicyl vinyl radical intermediate by
´
a metalloradical-mediated process. Unexpectedly, subsequent hydrogen atom transfer (HAT) from
the hydroxyl moiety to the vinyl radical leads to formation of an o-quinone methide intermediate.
This intermediate dissociates immediately from the metal center. This then undergoes an endocyclic,
sigmatropic ring-closing to give the chromene (Scheme 2a). This was confirmed by EPR experiments
and radical poisoning experiments using the 2,2,6,6-tetramethyl-1-piperidinyloxylyl (TEMPO) free
radical. This reaction inspired us to extend the protocol to related ring-closing reactions, but this time
using a nitrene precursor instead of a carbene precursor. This was expected to produce heterocycles
like benzoxazines, which find applications in the pharmaceutical industry (Scheme 2b). The reactions,
however, take a different course than expected and these unexpected results of the investigations are
disclosed in this paper.
Scheme 2. Proposed mechanism of previously reported catalytic 2H-chromene formation based on
DFT calculations (a); and the envisioned related pathway for the synthesis of benzoxazines using
ortho-hydroxy-aryl azides (b).
2
. Results and Discussion
2
.1. Experimental Studies
As an initial test reaction, o-azidophenol
presence of phenyl acetylene, expecting formation of benzoxazine
1
was reacted with CoP1 (Figure 1) in the
as the product (Scheme 3).
was not detected. Instead,
2
However, on analyzing the crude reaction mixture the expected product
2
1
new H-NMR peaks were detected, and the azide was fully consumed. The main product in the

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reaction was separated from the reaction mixture by column chromatography, and proved to be
phenoxizinone 3 (Scheme 3).
Figure 1. Different cobalt(II) porphyrins employed in this study.
Scheme 3. Formation of phenoxizinone 3 from o-azidophenol 1 and CoP1.
The unexpected formation of product 3 can be rationalized by considering HAT from the hydroxyl
group in the ortho-position of the cobalt(III) nitrenoid intermediate formed on activation of the azide
by the catalyst CoP1. This should result in the formation of the reactive ortho-imino-quinonoid
compound
4
(Scheme 4). Attack of the imine N atom of
4 on the para position (w.r.t to the carbonyl
group) of another molecule of
4, followed by 1,5-sigmatropic migration of a H atom, subsequent
deprotonation and oxidation would lead to formation of the phenoxazine product 3. Such a pathway
using ortho-aminophenol (OAP) has been reported before using manganese porphyrins that use H O
2
2
as the external oxidant [36]. In our case, the deprotonation and oxidation steps probably took place in
air during column chromatography.
Scheme 4. Proposed mechanism for formation of 3 from 1 mediated by CoP1.

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Compound
3
has anti-inflammatory and immunomodulatory properties and is, therefore,
valuable for its medicinal properties. As mentioned before, other reported methods involving
metalloporphyrin-catalyzed synthesis of from OAP make use of more powerful oxidants like
hydrogen peroxide, and are believed to be formed via different mechanisms [36].
To see if formation of could be avoided by using an excess of the alkyne, the reaction was also
performed in neat alkyne. However, also in this case almost exclusive formation of compound was
observed. In addition to that, simple aziridination of alkenes like cyclohexene and styrene were also
attempted using o-azidophenol , which in all cases led to formation of only one identifiable and major
3
3
3
1
product, the phenoxizinone 3 (Table 1).
Table 1. Reaction of o-hydroxy phenyl azide
1
with different substrates under reaction conditions a,b,*.
Entry
Substrate
Expected Product(s) Obtained Product
1
2
3
*
Reaction conditions: a: 0.5 mmol of azide
1
, 1 mmol of substrate, 5 mol% CoP1 (w.r.t. azide), 4 mL toluene,
˝
b
˝
5
0
C, 18 h; : 0.6 mmol of azide
1, 15 mL of substrate, 5 mol% CoP1, 50 C, 18 h. These different reaction
a,b
conditions ( ) gave identical results. No nitrene transfer to the solvent (toluene) was observed in any case
under the applied reaction conditions.
To be able to trap the proposed reactive intermediate
protect the phenyl ring on the 5-position, so that coupling of two iminoquinones to give products like
is prevented. As such, 2-azido-5-nitrophenol was synthesized. As a test reaction we tried to trap
4 with a different substrate we decided to
3
5
the corresponding o-quinone monoamine intermediate with 1-butoxyethene in an Inverse Electron
Demand Diels Alder (IEDDA) reaction (Scheme 5). For this transformation, however, no fruitful
results were obtained when using CoP1 as the catalyst. The crude reaction mixtures showed formation
of a mixture of products containing a lot of azide starting material. This is most likely due to the
inherent inability of CoP1 to activate the azide under the applied reaction conditions. However,
on switching to CoP2, the desired transformation could be achieved and product
6 was obtained in
80% yield. Non-catalytic trapping of o-quinone monoimines has been reported earlier, but the method
uses stoichiometric amounts of halogen containing oxidants, which is avoided in the reaction depicted
in Scheme 5 [37].
Scheme 5. Trapping of the o-quinone monoimine in an IEDDA reaction.

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Substrate
5
was also tested in reactions with other potential reaction partners, in which we
expected to be able to trap the iminoquinone intermediate with different C=C and C
”
C bonds (Table 2).
With phenyl acetylene no reaction involving the C C bond was observed. Other alkenes also proved
”
unreactive in this process. Apparently, only electron rich alkenes like 1-butoxyethene are suitable
reaction partners in this process.
Table 2. Reaction of azide 5 with different substrates a,b,*
.
Entry
Substrate
Expected Product(s)
Obtained Product
1
(~10%)
2
3
—
(
(80%)
4
—
a
˝
*
Reaction conditions: 0.5 mmol of azide
1
, 1 mmol of substrate, 5 mol% CoP2 (w.r.t. azide), 4 mL toluene, 50 C,
b
˝
1
8 h. 0.6 mmol of azide
1
, 15 mL of substrate, 5 mol% CoP2, 50 C, 18 h. These different reaction conditions
a,b
(
) gave identical results. No nitrene transfer to the solvent (toluene) was observed in any case under the
applied reaction conditions.
To investigate the generality of the observed HAT reactivity, we decided to explore the reactivity
of aryl azide
o-amino phenylazide
the catalyst (Scheme 6). In contrast to our expectations, however, azabenzene
7, containing an NH substituent in the ortho-position instead of an OH substituent. The
2
7
was synthesized and tested under the same reaction conditions, using CoP1 as
was obtained as the
8
major product. This observation intrigued us, as formation of aza compounds as products in reaction
of azides with cobalt(II) porphyrin catalyzed processes has been reported only once before, and only
as a minor side product [38].
Scheme 6. Reaction of o-aminophenyl azide 7 with cobalt(II) porphyrin catalyst CoP1.
Two mechanistic proposals for formation of aza compounds in cobalt(II) porphyrins catalyzed
reactions have been suggested: (I) Attack of the azide starting compound on the nitrene intermediate,
producing azabenzene with simultaneous N -loss, and (II) dinuclear N-N coupling involving two
2
nitrene complexes (Scheme 7).

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Scheme 7. Proposed mechanisms for formation of aza compounds in cobalt(II) porphyrin catalyzed
reactions with organic azides.
It is not so clear which reaction conditions lead to the formation of azabenzenes and which not.
One suggested possibility was that in the presence of a large excess of another reaction partner, the
concentration of the nitrene intermediate cannot build-up in a sufficient manner to allow formation of
aza compounds via dinuclear N–N coupling [39]. To check this hypothesis, we repeated the reaction of
azide
once again the aza compound
is something unique about the NH substituent in azide
7
in the presence of a large excess of phenyl acetylene or styrene in refluxing toluene. However,
was obtained as the major product. This led us to believe that there
that relates to formation of only the aza
8
7
2
compound. We speculate that this relates to rapid formation of o-phenylenediimine (OPDI) undergoing
further reactions to form 8.
The formation of azabenzene
diimine intermediate can be reasoned in the mechanism depicted in Scheme 8. Activation of azide
by the cobalt(II) catalysts leads to formation of a reactive nitrene radical intermediate. Subsequent
rapid HAT from the ortho-NH group to the nitrene radical moiety in this intermediate produces OPDI.
8 from ortho-aminophenyl azides via the proposed phenylene
9
7
2
This is followed by intermolecular coupling of two OPDI molecules to form aza compound 8. The ODPI
coupling steps could also be catalyzed by trace amounts of orthophenylenediamine (generated by
some minor side-reaction), as has been suggested in literature [40].
Scheme 8. Proposed mechanism of formation of azabenzene
8 from azide 7 involving the
intermediate OPDI.

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It is worth mentioning that this reaction of ortho-amino substituted phenyl azides to give the
azabenzene compounds as the major product is one of the few catalytic examples reported so far to
synthesize aza compounds in high yields [41–43]. An example involving a ruthenium metallo-radical
system proceeds via a free nitrene intermediate and works catalytically only for aryl azides with
electron rich substitutents like OMe and OEt [43]. Another iron based example is limited in the sense
that only azides with bulky substitutents like mestiyl groups result in formation of aza compounds [41].
With trifluoromethyl and methyl substituents dimers of the metal complex are obtained. The other
example involves a nickel complex, but this system produces only stoichiometric amounts of aza
compounds [42].
2
.2. Computational Studies
To estimate the reaction barriers for the assumed facile HAT process from the ortho-YH substituent
(Y = O, NH) to the nitrene moiety, we investigated this process with DFT for both the OH and the
NH substituents.
2
Starting from the cobalt(III) nitrene radical species the intramolecular HAT reaction of the
cobalt(III)nitrene radical of the azide was found to proceed via a 6-membered transition state,
5
further stabilized by a hydrogen bonding interaction between the transferred hydrogen atom and
a pyrrole nitrogen atom of the porphyrin (Figure 2, Computational details in Table S1). The barrier is
´
1
very low (+1.0 kcal
¨
mol ), thus explaining the experimental observations. Overall, the HAT process
´
1
is exergonic by ´10.8 kcal¨ mol
.
Figure 2. The DFT calculated barrier for HAT from the ortho hydroxyl group to the nitrene moiety.
˝
in kcal¨ mol´1, calculated at the BP86, def2-TZVP level with dispersion corrections.
∆
G
2
98K
We further evaluated the changes in spin density distribution (see Figure 3 and Table 3) during
the HAT process (see also Figure 2). The spin density distribution of the transition state is very similar
to that in the initial cobalt(III) nitrene radical, but after the HAT barrier and transfer of the hydrogen
atom from the –OH group, most of the spin density moves back to cobalt (Figure 3 and Table 3).
Simultaneously, the bond length of the Co-N bond elongates from 1.818 Å in the nitrene radical to
1
.923 Å in the imide as depicted in Table 4.

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(
2A)
Figure 3. Changes in the spin density distribution during the HAT process shown in Figure 2.
Table 3. Changes of the N, O and Co atom spin populations during the HAT process shown in Figure 2.
(2B)
(2C)
Atom
2A
2B
2C
Co
N
O
11.1%
39.6%
5.3%
8.5% 60.6%
33.5% 16.1%
10.0% 9.4%
Table 4. Relevant bond length (Å) changes during the HAT process shown in Figure 2.
Structure Co–N N–C C–C C–O N–H
2
2
2
A
B
C
1.81769 1.32018 1.47138 1.34208 1.86203
1.81731 1.31667 1.48868 1.30627 1.33591
1.92289 1.32157 1.50424 1.24441 1.03461
The almost barrierless abstraction of a neighboring hydrogen atom by the reactive cobalt(III)
nitrene radical thus prevents any intermolecular coupling reactions of the nitrene moiety with exogenous
substrates. A similar process was also calculated for the NH substituted azide, and once again the
2
barrier for intramolecular HAT between the NH group and the nitrene moiety was found to be low
2
´
1
(
see Figure 4). The free energy required to reach the transition state is only +9.1 kcal mol implying
that this intramolecular process is fast, even at room temperature. The overall transformation is
¨
exergonic by ´3.1 kcal¨ mol´
1
.
Figure 4. The DFT calculated barrier for HAT from the ortho-amino group to the nitrene moiety.
˝
in kcal¨ mol´1, calculated at the BP86, def2-TZVP level with dispersion corrections.
∆
G
2
98K

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The computed changes in the spin density distributions are once again in line with the HAT
process, and similar to those computed for HAT from the OH substituent (See Figure 5 and Table 5).
During the HAT process the spin population shifts from the nitrene radical in 3A to cobalt in 3C, and
after the HAT process the spin density is mostly concentrated at the cobalt atom. The bond distance
analysis of the relevant bonds are shown in Table 6. Here the Co-N bond in the final structure elongates
from 1.8521 Å in the transition state 3B to 1.9604 Å in the final structure 3C. Interestingly, the adduct
remains coordinated to the cobalt complex, as is evident from the bond distances.
(
3A)
Figure 5. Changes in spin density distribution for HAT depicted in Figure 4.
Table 5. Changes of the N, O and Co atom spin populations during the HAT process shown in Figure 4.
(3B)
(3C)
Atom
3A
3B
3C
Co
N
O
8%
36%
10%
11%
24%
20%
63%
10%
9%
Table 6. Relevant bond length (Å) changes during the HAT process shown in Figure 4.
Structure Co–N N–C C–C C–N N–H
3
3
3
A
B
C
1.8411 1.3161 1.4835 1.3576 2.1848
1.8521 1.3126 1.5060 1.3262 1.3213
1.9604 1.3152 1.5022 1.4378 1.0340
While the barrier for the HAT process depicted in Figure 4 is low, it is not barrierless. Hence,
to exclude the possibility of intermolecular coupling of the nitrene radical to phenyl acetylene (see
Scheme 2b) being in competition with the intramolecular HAT process (Figure 4), we decided to make
a direct computational comparison of the two processes. Attack of the porphyrin cobalt(III) nitrene
radical on the alkyne to form the
DFT level (see Figure 6). The latter process is exergonic (
γ
-radical species 4C
(
C’ in Scheme 2b) was computed at the same
´
1
´
10.8 kcal mol ), but has a computed barrier
¨
´
1
´1
of +13.4 kcal
¨
mol . This barrier is almost 4 kcal
¨
mol higher than the barrier for intramolecular
HAT (see Figure 4), and hence this process cannot efficiently compete with the intramolecular HAT
reaction. Formation of the OPDI intermediate by HAT is expected under all reaction conditions.
The spin density distribution changes were once again calculated for the structures 4A
. Interestingly, in contrast to the structures shown in Figures 3 and 5 the spin density in structure 4C
is strongly delocalized over the carbon atoms of the -alkyl radical and the adjacent phenyl ring, with
barely any spin density at the cobalt atom (see Figure 7).
, 4B and
4
C
γ

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Figure 6. DFT computed reaction barrier for attack of the cobalt(III) nitrene radical on phenyl acetylene
˝
´1
leading to formation of a
def2-TZVP level with dispersion corrections.
γ
-alkyl radical intermediate.
∆
G
in kcal
98K
¨
mol computed at the BP86,
2
(
4A)
(4B)
(4C)
Figure 7. Changes in spin density distributions during the HAT depicted in Figure 6.
. Experimental Section
3
3
.1. General Information
All chemicals were purchased from commercially available sources unless otherwise mentioned.
Solvents for reactions that were performed in inert conditions were freshly distilled from sodium and
1
degassed prior to use. All NMR spectra for these experiments were recorded at 293 K. For H-NMR
a 400 MHz Avance 400 (Bruker, Karlsruhe, Germany) or a 300 MHz Advance 300 machine (Bruker,
Karlsruhe, Germany) was used. These spectra were referenced internally to residual solvent resonance
= 7.26 ppm) or DMSO (2.50). For 13C{ H}-NMR a Bruker Avance 400 (101 MHz) or Bruker
1
of CDCl3 (
δ
Avance 500 (126 MHz) machine was used. These spectra were referenced internally to residual solvent
resonance of CDCl3 ( = 77.2 ppm) or DMSO-d (39.5). UV-vis spectra were recorded on a Hewlett
Packard 8453 spectrophotometer (Waldbronn, Germany).
δ
6
3
.2. Synthetic Details
Compounds
matched those reported.
1 [1] and 7 [2] were prepared according to literature reports and their analytical data

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3
.2.1. Synthesis of 2-Azido-5-nitrophenol (5)
-Amino-5-nitrophenol (72.4 mmol) was added to aq.HCl (6 M, 100 mL) at 0 C. To this a solution
˝
2
of NaNO (96.5 mmol) in water (20 mL) was added dropwise. After stirring this mixture for 5 min
2
sodium azide (96.5 mmol) that was predissolved in water (60 mL) was added dropwise and stirred
for 45 min. The precipitate was extracted with chloroform and then washed with water. The organic
layer was dried over MgSO . On evaporation of the solvent a dark pink brownish solid was obtained
4
(
80% crude yield). This was purified further by flash chromatography over silica (EtOAc-Hex = 1:1) to
1
give a dark pink solid (75% yield). H-NMR (400 MHz, chloroform-d)
7
δ
7.87 (dd, J = 8.7, 2.5 Hz, 1H),
147.46,
.80 (d, J = 2.5 Hz, 1H), 7.19 (d, J = 8.7 Hz, 1H), 5.65 (s, 1H). 13C-NMR (75 MHz, chloroform-d)
δ
1
45.53, 133.08, 118.25, 116.92, 111.66.
3
.2.2. Synthesis of the Catalyst CoP2
Perfluorinated tetraphenylporphyrin TPPH2F20 (0.5 mmol, 480 mg) was refluxed in acetic acid
300 mL) with an excess of CoCl2 6H O (2.6 mmol, 620 mg) and sodium acetate (15 mmol, 1.24 g)
(
¨
2
for 1 h. The mixture was allowed to cool down and the solvent was evaporated until most solids
precipitated out. The red solids thus obtained were washed with water, aqueous sodium bicarbonate
and finally with a minimum amount of cold methanol. The solid was then dried in-vacuo to give CoP2
(90% yield). UV-vis spectrum (THF), λmax/nm: 408, 520, 558.
3
.2.3. Catalytic Reaction of Compound 1 to Give Product 3
In a flame dried Schlenk flask loaded with a stirrer 1 mmol of
1 was added followed by
0
.05 mmol of CoP1. The Schlenk flask was then evacuated and refilled with nitrogen (three times).
˝
Subsequently 4 mL of dry chlorobenzene was added, and the flask was thermostatted at 50 C for 18 h.
After evaporating the solvent the mixture was directly loaded on a silica gel column. The product was
1
eluted with Hex:EtOAc (1:1) to give product
3
in 80% isolated yield. H-NMR (400 MHz, Chloroform-d)
δ
7.79–7.72 (m, 1H), 7.45 (ddd, J = 8.3, 6.9, 1.6 Hz, 1H), 7.42–7.32 (m, 2H), 6.48 (s, 1H), 6.42 (s, 1H),
5
.11 (s, 2H). 13C-NMR (75 MHz, CDCl3)
δ
180.00, 149.72, 142.25, 133.23, 129.59, 128.29, 125.05, 115.56,
1
14.24, 103.61.
For the other reactions of compound
also see the footnote in Table 1).
1
with other substrates, the same stoichiometry was used
(
3
.2.4. Catalytic Reaction of Compound 5 to Give Product 6
In a flame dried Schlenk flask loaded with a stirrer 1 mmol of
5 was added followed by
0
.05 mmol of CoP2. The Schlenk flask was then evacuated and refilled with nitrogen (three times).
˝
Subsequently 4 mL of chlorobenzene was added, and the reaction was thermostatted at 50 C for 18 h.
After evaporating the solvent, the mixture was directly loaded on a silica gel column. The product
1
was eluted with Hex:EtOAc (1:1) to give product
6
in 80% yield. H-NMR (300 MHz, Chloroform-d)
δ
7.82–7.65 (m, 2H), 6.53 (d, J = 8.7 Hz, 1H), 5.27 (t, J = 2.4 Hz, 1H), 4.57 (s, 1H), 3.85 (dt, J = 9.7, 6.7 Hz,
1
1
1
H), 3.62 (dt, J = 9.7, 6.6 Hz, 1H), 3.58–3.46 (m, 1H), 3.51–3.38 (m, 1H), 1.54 (dq, J = 8.6, 6.8 Hz, 2H),
13
.29 (dt, J = 14.9, 7.4 Hz, 3H), 0.86 (t, J = 7.4 Hz, 4H). C-NMR (75 MHz, CDCl )
δ 140.14, 139.16, 138.81,
3
19.53, 113.78, 112.78, 93.85, 68.60, 44.42, 31.54, 19.25, 13.86.
For the other reactions of compound
also see footnote in Table 2).
5 with other substrates, the same stoichiometry was used
(
3
.2.5. Catalytic Reaction of 7 to Give Compound 8
In a flame dried Schlenk flask loaded with a stirrer compound 7 (67 mg, 0.5 mg) and CoP1 (17 mg,
0
.025 mmol) was added and the flask was evacuated and backfilled with dinitrogen (three times).
˝
Subsequently 4 mL of PhCl was added, and the reaction mixture was thermostatted at 50 C for 18 h.

Molecules 2016, 21, 242
13 of 16
The reaction mixture was then subjected to preparative TLC and a bright orange band was obtained
which was analyzed and found to be compound 8.
3
.2.6. Catalytic Reaction of Aminophenyl Azide 7 to Give 8
In a flame dried Schlenk flask loaded with a stirrer compound 7 (67 mg, 0.5 mg) and CoP1 (17 mg,
0
.025 mmol) were added and the flask was evacuated and backfilled with dinitrogen (three times).
˝
Subsequently 4 mL of PhCl was added. The reaction mixture was then thermostatted at 50 C for 18 h.
The resulting mixture was subjected to preparative TLC and a bright orange band was obtained which
1
was analyzed and found to be compound
8
. H-NMR (400 MHz, Chloroform-d)
δ
7.68 (dd, J = 8.0,
143.11,
13
1
1
.6 Hz, 1H), 7.23–7.06 (m, 1H), 6.93–6.63 (m, 2H), 5.48 (s, 2H). C-NMR (126 MHz, CDCl )
δ
3
37.73, 131.37, 124.29, 117.66, 117.04.
3
.3. Computational Details
Geometry optimizations were carried out with the Turbomole program package [44] coupled to
the PQS Baker optimizer [45 46] via the BOpt package [47] at the DFT level using the b3-lyp [48–50]
,
functional and def(2)-TZVP basis set [51] for the geometry optimizations of all stationary points.
Grimme’s D3 dispersion corrections were used in all calculations (disp3, zero damping) [52].
All minima (no imaginary frequencies) and transition states (one imaginary frequency) were
characterized by numerically calculating the Hessian matrix. ZPE and gas-phase thermal corrections
(entropy and enthalpy, 298 K, 1 bar) from these analyses were calculated.
4
. Conclusions
While trying to employ ortho-YH substituted phenyl azides (Y = OH, NH ) as substrates in
2
nitrene transfer reactions catalyzed by cobalt(II) porphyrins, we discovered that the hydrogen
atom of the YH moiety is readily abstracted by the reactive cobalt(III) nitrene radical intermediate.
This leads to formation of reactive intermediates like o-quinone monoimines (OQMI; Y = OH) and
orthophenylinendiimines (OPDI; Y = NH ). These reactive compounds rapidly undergo several
2
follow-up reactions (Scheme 9), thus preventing any direct (radical-type) coupling reactions of the
nitrene radical intermediate with C=C or C
Y = OH) easily dimerize and produce phenoxizinone
of 1-butoxyethene the o-quinone monoimine can also be trapped in an IEDDA reaction, producing
benzoxazine . Formation of orthophenylinendiimine (OPDI) from ortho-NH -phenylazide (Y = NH )
is also associated with hydrogen atom abstraction of the Co(III) nitrene radical from the NH2
substituent in the ortho position. As a result, aza compound is obtained. Attempts to react ortho
”
C bonds of other substrates. The o-quinone monoimines
(
3
under aerobic conditions. In the presence
6
2
2
8
substituted azides with other reaction partners by altering the reaction conditions were not successful.
DFT computations are in agreement with the experiments; HAT from the ortho-YH substitutent (Y= O
or NH) to the nitrene moiety has a (very) low barrier in both cases.
The observed facile HAT from the ortho-YH substitutent (Y= O or NH) to the nitrene moiety is
perhaps a potential disadvantage of using these systems, as it prevents the initially anticipated
radical-type coupling of the cobalt(III) nitrene radical intermediate to C=C and C C bonds of
”
other substrates. On the other hand, it does provide a rather mild route to prepare highly reactive
o-iminoquinonoids and o-phenylenediimines which can be employed in several follow up reactions.
At the same time, the possibility of further reactivity of these intermediates occurring in the coordination
sphere of the catalyst cannot be ruled out at the moment and might even be plausible based on the bond
distance data that we obtained from the DFT optimized structures of these compounds after HAT.
This suggests that diastereo- or enantioselective reactions may be accessible in synthetically useful
transformations [42], mediated by chiral cobalt catalyst. This is a current topic of investigations in
our group.

Molecules 2016, 21, 242
14 of 16
Scheme 9. Transformations observed in this study.
Supplementary Materials: Details of the newly synthesized compounds and catalytic reactions are available
online at http://www.mdpi.com/1420-3049/21/2/242/s1. See the Supporting Information (SI) for NMR spectra
and DFT tables.
Acknowledgments: Financial support from the Netherlands Organization for Scientific Research (NWO-CW VICI
project 016.122.613) and the University of Amsterdam is gratefully acknowledged.
Author Contributions: M.G. and B.B. conceived and designed the experiments. M.G. performed the experiments
and part of the calculations. C.R. performed calculations and interpreted computational data. M.G. and B.B. wrote
the paper.
Conflicts of Interest: The authors declare no conflict of interest.
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