Metal-porphyrin catalyzed aziridination of α -methylstyrene: Batch v s. flow process

Article abstract of DOI:10.1142/S1088424617500365

This work describes the aziridination process of α-methylstyrene by using electron poor aromatic azides in the presence of metal-based porphyrins as catalysts. Different ruthenium and cobalt-based porphyrins were successfully employed for the synthesis of

Full text of DOI:10.1142/S1088424617500365

Journal of Porphyrins and Phthalocyanines
J. Porphyrins Phthalocyanines 2017; 21: 1–10
DOI: 10.1142/S1088424617500365
Published at http://www.worldscinet.com/jpp/
Metal-porphyrin catalyzed aziridination of α-methylstyrene:
Batch vs. flow process
Daniela Intrieri*, Sergio Rossi*, Alessandra Puglisi and Emma Gallo
Dipartimento di Chimica, Università Degli Studi di Milano, Via Camillo Golgi 19, 20133 Milano, Italy
Dedicated to Professor Claudio Ercolani on the occasion of his 80th birthday
Received 20 January 2017
Accepted 16 March 2017
ABSTRACT: This work describes the aziridination process of α-methylstyrene by using electron poor
aromatic azides in the presence of metal-based porphyrins as catalysts. Different ruthenium and cobalt-
based porphyrins were successfully employed for the synthesis of N-aryl aziridines performed under
a traditional batch methodology and under continuous flow conditions. In general, yields obtained
using ruthenium-based catalysts in a traditional batch process were higher than those observed when
the reaction was performed under flow conditions. However, cobalt-based porphyrins showed better
activities and short reaction times when employed in a flow system process. DFT calculations were also
performed in order to understand the influence of substituents on the porphyrin ring in the aziridination
process.
KEYWORDS: homogeneous catalysis, ruthenium, cobalt, aziridination, azide, flow chemistry.
in order to optimize the reaction efficiency. Following on,
INTRODUCTION
organic azides (RN3) represent a versatile class of reactants
Considering the biological and/or pharmaceutical
which are very reactive toward different substrates and are
importance of nitrogen containing molecules, the
easily synthesized from commercially available amines
scientific community is always interested in developing
[16–19]. Moreover, they generate the nitrene moiety (RN)
new synthetic methodologies to obtain them in good yields
with the contemporary formation of benign N2 as the only
and selectivities [1]. Among all reagents employed for the
stoichiometric by-product (Scheme 1).
synthesis of aza-derivatives, aziridines are extensively
The use of organic azides as starting materials have
used as building block in organic synthesis thanks to
been restricted due to their hazardous nature, thus more
the high reactivity of the strained three-membered rings,
stable compounds were preferred. However more recent
which can easily be involved in ring opening reactions
continuous flow methodologies are being applied to
[2–7]. Among all the synthetic available procedures
minimize this limitation [20]. This approach provides
yielding aziridines, the metal-catalyzed nitrene transfer
safe handling of hazardous reagents by using small
reaction to unsaturated hydrocarbons represents a valuable
amounts of chemicals with a consequent decrease of the
strategy to obtain this class of compounds [8–10].
process risks and a shortness of reaction times.
The use of imidoiodinane compounds (R′I = NR) as
We recently reported the use of continuous flow
nitrogen sources have been extensively studied [11–15], but
methodologies for the aziridination of styrenes by using
several drawbacks related to their use encouraged scientists
to investigate the reactivity of alternative starting materials
aromatic azides as nitrene sources and Ru(TPP)CO
(TPP = dianion of tetraphenyl porphyrin) as the reaction
catalyst [21, 22]. In order to expand our recent study
of the catalytic reaction of aryl azides with styrenes
affording N-aryl aziridines, we focused our attention
on the use of different metal-based porphyrins by
*Correspondence to: Daniela Intrieri, email: daniela.intrieri@
unimi.it; Sergio Rossi, email: sergio.rossi@unimi.it, tel: +39
025-031-4371
Copyright © 2017 World Scientific Publishing Company

2
D. INTRIERI ET AL.
(3a), which presents unsubstituted meso-phenyl groups
and only small differences of the catalytic efficiency
were observed by using ruthenium porphyrin catalysts
showing differently substituted meso-aryl groups. The
lowest yield was registered in the presence of catalyst
3d (Table 1, entry 7) where steric effects became more
evident due to the presence of two CF3 groups on meta
positions of meso-aryl groups.
Scheme 1. General route for the aziridinations of alkenes by
organic azides
applying continuous flow techniques. With this purpose,
we systematically investigated how electronic and/or
steric features of porphyrin complexes influence their
catalytic activity. Herein we report the use of different
metal porphyrins in promoting aziridination reactions in
flow conditions as well as the comparison of achieved
data with those obtained working in batch conditions. In
addition, achieved experimental results were supported
by a DFT investigation of reported catalytic reactions.
Cobalt porphyrin complexes 3g–3i demonstrated to
be less catalytically active in batch conditions (Table 2)
than ruthenium complexes and longer reaction times and
lower yields were generally observed.
A better catalytic performance was usually observed
for the synthesis of aziridine 4a independently from the
electronic and steric nature of the porphyrin ligand. On
the other hand, low yields registered in the synthesis of
4b were probably due to the lower chemical stability
of 3,5-bis(trifluoromethyl)phenyl azide 2a in refluxing
benzene when the catalytic reaction was run for a long
time to reach complete azide conversion.
RESULTS AND DISCUSSION
Inordertoimprovetheefficiencyof4aand4bsynthesis
catalyzed by ruthenium and cobalt porphyrin-complexes,
we performed reactions described above under flow
conditions. We realized a simple 500 mL microreactor
using a PolyTetraFluoroEthylene (PTFE) HPLC tubing
(see the Supporting information section for further
details). The flow apparatus was settled up as illustrated
in Scheme 3, and the reactions were performed under
previously identified standard conditions [21]. A Chemix
Fusion syringe pump equipped with two 2.5 mL Hamilton
gastight syringes was used to feed the microreactor with
the reagents through a T-junction (Syringe A: 0.008 M
solution of catalyst in α-methylstyrene as the solvent;
Syringe B: 0.4 M azide solution in α-methylstyrene
as the solvent, biphenyl as the internal standard). The
microreactor was coiled in a bundle and immersed in a
In order to study the electronic and steric influence of
porphyrin ligands on the catalytic activity of ruthenium
and cobalt complexes, we tested different catalysts 3a–3i
listed in Scheme 2 in the aziridination of α-methylstyrene
(1), by using either 3,5-bis(trifluoromethyl)phenyl azide
(2a) or 4-nitrophenyl azide (2b) as the aminating agent.
Ruthenium porphyrin complexes [23–25] 3a–3f effi-
ciently promoted the synthesis of both aziridines 4a and
4b in batch conditions (Table 1). The synthesis of 4a
occurred with slightly lower yields than those already
achieved for 4b [23], however a decrease in reaction
times was generally observed. As reported in Table 1, the
efficiency of the synthesis of 4a did not strongly depend
on electronic and steric characteristics of the porphyrin
catalyst. The desired aziridine 4a was formed in 94%
yield (Table 1, entry 1) in the presence of Ru(TPP)CO
Scheme 2. Complexes 3a–3i-catalyzed aziridination of α-methylstyrene by either 3,5-bis(trifluoromethyl)phenyl azide (2a) or
4-nitrophenyl azide (2b)
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METAL-PORPHYRIN CATALYZED AZIRIDINATION OF α-METHYLSTYRENE: BATCH vs. FLOW PROCESS
3
a
Table 1. In a typical run, the opportune catalyst (1.20 × 10-5
mol) the opportune azide (6.00 × 10-4 mol) and α-methylstyrene
(2.50 × 10-3 mol) were added to benzene (25 mL) in a Schlenk
flask. b Time required for complete conversion of the starting
azide monitored by IR spectroscopy. c Determined by 1H NMR
employing 2,4-dinitrotoluene as the internal standard
120°C preheated oil bath. Conversion was determined by
GC analysis of the crude mixture collected after 30 min
at -30°C. Results are reported in Table 3.
Aziridine 4a was obtained in high yields when either
Ru(TPP)CO (3a) or Ru(OEP)CO (3b) (OEP = dianion
of octaethyl porphyrin) were employed as catalysts
(Table 3, entries 1–2) whilst, as expected, lower yields
where observed when less active azide 2b was employed
as the starting material. These data are in agreement with
those obtained in batch condition, where compound 2b
required longer reaction time in order to form product 4b
in a quantitative yield (Table 1, entries 1–2).
The use of sterically hindered catalyts such as Ru(β-
Br4TPP)CO (3c) (β-Br4TPP = dianion of 2,3,12,13-
tetrabromo-tetraphenylporphyrin) or Ru(3,5(CF3)2TPP)
CO (3d) (3,5(CF3)2TPP = dianion of tetrakis(3,5-
bis(trifluoromethyl)phenyl)porphyrin), bearing electron
withdrawing groups on the porphyrin ring, caused a
decrease in yields and product 4a was obtained with 67%
and 49% yield, respectively. A small decrease in terms
of yields was also observed when the more electron rich
ruthenium porphyrin catalyst 3e was used, leading to the
formation of the desired product with 82% yield (Table 3,
entry 5). This negative catalytic effect was also observed
when a xylene residue was present on the meso-position
of catalyst 3f and aziridine 4a was obtained in only 69%
yield (Table 3, entry 7).
A general lower reactivity was observed when
4-nitrophenylazide(2b)wasemployedintheaziridination
of α-methylstyrene performed under continuous flow
conditions, where only catalysts Ru(TPP)CO (3a) and
Ru(OEP)CO (3b) led to the formation of corresponding
product 4a in good yields (Table 3, entries 1–2). Catalyst
Ru(β-Br4TPP)CO (3c) afforded the desired product
with 48% yield, but the most electron poor catalyst
Ru(3,5(CF3)2TPP)CO (3d) seemed not to be effective in
the reaction involving 4-nitrophenyl azide (2b) (Table 3,
entry 4). However, clear evidence of these results showed
that only Ru(TPP)CO (3a) and Ru(OEP)CO (3b)
catalysts were able to preserve their catalytic efficiency
when employed under flow conditions.
Entrya
1
Catalyst
Time, hb
0.5
Yield, %c
Ru(TPP)CO (3a)
4a
94
2
3
0.75
0.5
4b
4a
99
94
Ru(OEP)CO (3b)
4
5
1.5
0.5
4b
4a
96
86
Ru(β-Br4TPP)CO (3c)
Ru(3,5(CF3)2TPP)CO (3d)
Ru(4nBuTPP)CO (3e)
Ru(TMP)CO (3f)
6
7
0.5
0.5
4b
4a
98
78
8
9
1
4b
4a
98
88
0.5
10
11
1
4b
4a
99
92
0.5
12
2
4b
95
a
Table 2. In a typical run, the opportune catalyst (1.20 × 10-5
mol) the opportune azide (6.00 × 10-4 mol) and α-methylstyrene
(2.50 × 10-3 mol) were added to benzene (25 mL) in a Schlenk
flask. b Time required for complete conversion of the starting
azide monitored by IR spectroscopy. c Determined by 1H NMR
employing 2,4-dinitrotoluene as internal standard
Entrya
1
Catalyst
Time, hb
1
Yield, %c
Co(OEP) (3g)
4a
51
8
4b
4a
46
56
2
3
Co(TPP) (3h)
3.5
16
4
4b
4a
4
Co(TMOP) (3i)
41
15
4b
10
Scheme 3. Reaction between azides 2a–2b and α-methylstyrene 1 promoted by ruthenium and cobalt porphyrin complexes in a
two-syringe continuous-flow system by using a 500 mL mesoreactor
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D. INTRIERI ET AL.
Table 3. a In a typical run, A and B mixtures were fed into the
120°C pre-heated 500 mL PTFE mesoreactor using a syringe
pump (flow rate 8.333 mL/min; residence time 30 min). Mixture
A: catalyst (1.60 × 10-5 mol) in 2 mL of 1. Mixture B: azide
(8.00 × 10-4 mol), biphenyl as the internal standard (6.00 ×
10-5 mol) in 2 mL of 1. b Determined by GC employing biphenyl
as the internal standard
which increased up to 48% yield by means of the flow
approach (with 30 min of residence time). As a general
consideration, better results in terms of yields were also
obtained with other cobalt-based porphyrin catalysts.
Furthermore, the possibility to operate under flow
conditions presents the advantage of operating with
smaller reaction volumes and in the absence of solvent.
Entrya
Catalyst
Product 4a Product 4b
GC yield, GC yield,
b
b
DFT CALCULATIONS
%
%
1
2
3
4
5
6
Ru(TPP)CO
3a
3b
3c
98
97
67
49
82
69
64
70
48
14
38
21
Theoretical studies were also performed in order to
understand the influence of substituents on the porphyrin
ring in the aziridination process and to elucidate the
differences in terms of the energy barrier profile using
different ruthenium porphyrin complexes. Since it was
already established that ruthenium and cobalt-based
aziridinations occur through different mechanisms [26,
27], the two catalytic reactions were not compared and
the cobalt-catalyzed aziridination was not the object
of this DFT investigation. The overall energy profile
for the aziridination of α-methylstyrene (1) with 3,5-
bis(trifluoromethyl)phenyl azide (2a) catalyzed by ruthe-
nium porphyrin complexes was already investigated
[28] by means of kinetic studies and DFT calculations.
A general overview of the mechanism is reported in
Scheme 4. It is known that the first step of the mechanism
involves the coordination of the azide to ruthenium
complex A to form B. This coordination results in the
activation of the azide ArN3 and the consequent eco-
friendly dismissal of a neutral N2 molecule leading to
the formation of the diradical mono-imido [Ru](NAr)
(CO) complex C ([Ru] = ruthenium porphyrin) which,
depending on the reaction conditions, can be involved in
a singlet à triplet spin crossing process. Complex C(t),
in its triplet state can react with the incoming olefin and
transfer one of the nitrogen unpaired electrons to the distal
olefin carbon atom forming the metastable and diradical
N–C–C open chain complex D. Consequent minor
Ru(OEP)CO
Ru(β-Br4TPP)CO
Ru(3,5(CF3)2TPP)CO 3d
Ru(4nBu-TPP)CO
3e
3f
Ru(TMP)CO
Table 4. a In a typical run, A and B mixtures were fed into the
120°C pre-heated 500 mL PTFE mesoreactor using a syringe
pump (flow rate = 8.333 mL/min; residence time = 30 min).
Mixture A: catalyst (1.60 × 10-5 mol) in 2 mL of 1. Mixture B:
azide (8.00 × 10-4 mol), biphenyl as the internal standard (6.00 ×
10-5 mol) in 2 mL of 1. b Determined by GC employing biphenyl
as the internal standard
Entrya
Catalyst
Product 4a GC Product 4b GC
yield, %b
yield, %b
1
2
3
Co(OEP)
3g
3h
3i
69
66
73
52
48
36
Co(TPP)
Co(TMOP)
In order to improve the catalytic performance of the
aziridination of α-methylstyrene under flow conditions,
we then moved to the investigation of the catalytic
activity of cobalt porphyrin catalysts 3g–3i. Results are
reported in Table 4.
We were delighted to see that the use of cobalt-
base porphyrin catalysts for the aziridination of
α-methylstyrene under mesofluidic conditions presented
a beneficial effect in terms of yields, especially if
compared with their activity which was observed using
the traditional batch approach (Table 4 vs. Table 2).
Best results were obtained with catalyst Co(TMOP)
(3i) (TMOP = dianion of tetrakis(4-methoxyphenyl)
porphyrin) that afforded product 4a in 73% yield after
30 min of residence time. Even better results were
achieved with catalysts Co(OEP) (3g) and Co(TPP) (3h),
affording product 4a in comparable yields. Furthermore,
with this approach, 4-nitrophenyl azide (2b) also was
found to be reactive in the synthesis of aziridine 4b. It
can be noted that, in the presence of catalyst Co(OEP)
(3g) under traditional batch conditions, only traces
of product were isolated after 16 h (Table 2, entry 3)
Scheme 4. Overall mechanism of the [Ru](CO)-catalyzed
aziridination of α-methylstyrene by ArN3
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METAL-PORPHYRIN CATALYZED AZIRIDINATION OF α-METHYLSTYRENE: BATCH vs. FLOW PROCESS
5
stereochemical rearrangements of this latter compound
atom with the ruthenium atom) where the optimization
and calculation of the thermochemical properties were
performed with B97D functional [31], the effective
Stuttgart/Dresden core potential (SDD) was adopted for
the ruthenium atom and for all the other atomic species
the basis set applied was 6-31G(d). All the calculations
were performed in vacuum by using Gaussian G09 rev
D01 package [32]. The calculated energy profiles for the
generation of mono-imido complexes Ca–Cf are shown
in Fig. 1, energies values are reported in Table 5 and the
coordinates of all the optimized structures are described
in the Supplementary material (see the Supporting
information section).
As expected, the anchoring step of the Nα azide atom
of 2a to the metal center of the porphyrin was a favorite
process [28, 29] and a high stabilization was observed
when catalysts 3c and 3f (-4.20 kcal/mol and -4.15 kcal/
mol, respectively) were used. Interestingly, the performed
calculations showed that in all the cases investigated, the
energy barrier required for the generation of mono-imido
are finally responsible for the aziridine ring closure by a
spin coupling process. After the release of the aziridine
product from E, the initial ruthenium porphyrin complex
A is restored and available for a new catalytic cycle.
Considering that previous work established that
the high-demanding energy step (formally, the Rate-
Determining Step) involves the release of N2 molecule
[28, 29], we focused our attention in determining the
energy barrier of this step related to all the different
ruthenium porphyrins 3a–3f employed in this study.
Firstly, a conformational analysis with Monte Carlo
techniques, performed with OPLS_2005 force field [30]
on a simple model of all the structures analyzed below,
achieves the best conformation of differently substituted
porphyrin molecules (the ruthenium atom was replaced
with a generic octahedral six-coordinated atom for
simplicityofcalculations).Subsequently,alltheoptimized
structures were validated as minima or transition states
by DFT calculations (after the replacement of the generic
Fig. 1. Energy profile for the generation of mono-imido complexes Ca–Cf
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D. INTRIERI ET AL.
Table 5. Free energy values calculated at the B97D/6-31G(d) Ru(SDD) level of theory. All the transition states presented one
imaginary frequency.
Catalyst
Complex B
DG°, kcal/mola DG#, kcal/molb
B → C (TS) B → C barrier, Complex C(s) Complex C(t) DDG°
,
(t)
C(s)
kcal/mold
→
kcal/molc
DG°, kcal/mola DG°, kcal/mola
Ru(TPP)CO
3a
3b
3c
-1.53
-3.40
-4.20
-3.47
-2.86
-4.15
18.57
14.82
14.83
18.41
15.85
14.27
20.10
18.22
19.03
21.87
18.71
18.43
-11.22
-12.64
-11.48
-9.39
-15.63
-18.70
-17.16
-14.15
-17.51
-20.79
-4.41
-6.06
-5.68
-4.76
-5.31
-7.62
Ru(OEP)CO
Ru(β-Br4TPP)CO
Ru(3,5(CF3)2TPP)CO 3d
Ru(4nBu-TPP)CO
3e
3f
-12.20
-13.17
Ru(TMP)CO
aꢀDG° values represent the standard free energy of the corresponding ground state. bꢀDG# values represent the standard free energy of
the corresponding transition state. c The energy barrier was calculated as DG#–DGo. d Calculated as DG°C(t)–DG°C(s)
.
of electron donating substituents on the porphyrin ring
played a positive effect on the chemical efficiency of
the process, as confirmed by high aziridine 4a yields
observed in the presence of these catalysts by applying
traditional batch conditions (Table 1, entries 9 and 11).
The presence of electron withdrawing substituents, such
as the four bromine atoms of catalyst Ru(β-Br4TPP)CO
(3c), seemed to have a minor influence on the interaction
of azide 2a with the ruthenium complex, probably because
the distortion induced by substituents on the porphyrin
ring caused a less steric hindrance between the porphyrin
and the aromatic ring of the incoming azide. However,
the lower electron density present on the ruthenium atom
of the catalyst induces a small decrease of reaction yields
(Table 3, entry 3).
Surprising, Ru(TPP)CO (3a) presents an energy
barrier of 20.10 kcal/mol, that was +1.39 kcal/mol higher
than that calculated when the electron rich Ru(4nBuTPP)
CO (3e) was applied as the reaction catalyst. This could
be explained considering possible p-staking interactions
between hydrogen atoms of the porphyrin phenyl
substituents and the aromatic ring of the azide. The
analysis of the geometry of 3a and 3e transition states
revealed that only in the case of 3e, hydrogen atoms
in the ortho position of the phenyl ring were oriented
toward the aromatic ring of the azide with a consequent
stabilization of the interaction. On the other hand, the
absence of any stabilization process in the interaction of
3a with azide 2a explains the observed increase of the
energy barrier when 3a was applied (Fig. 3).
Fig. 2. Transition state structure related to the interaction of
catalyst 3f with azide 2a. Hydrogen atoms were omitted for
clarity
complexes C(s) was about 20 kcal/mol, in accordance
with that already reported by some of us and consistent
with the high temperature required for the catalysis to
proceed [28, 29].
Catalyst Ru(OEP)CO (3b) presented the lowest
energy barrier (18.22 kcal/mol) probably due to the
absence of steric interactions between the aromatic ring
of the 3,5-bis(trifluoromethyl)phenyl azide (2a) and the
hydrogen atoms on the meso-positions of the porphyrin
moiety. As showed in Fig. 2, the azide molecule was
perfectly hosted between the ethyl substituents of the
catalyst, the CF3 groups of the azide and the terminal
CH3 groups of the ethyl substituents on β-pyrrolic
porphyrin positions adopted an anti conformation, where
the shortest distance Hporp••••Fazide was about 2.6 A. This
situation was observed only when a β-substituted catalyst
interacts with the azide reactant.
The presence/absence of this kind of interaction was
confirmed by performing a non-covalent interaction (NCI)
analysis, using NCIPLOT software [33, 34]. NCI analysis
revealed that this type of interaction was also present in
the transition state of the coordination of azide 2a either
to Ru(β-Br4TPP)CO (3c) or Ru(TMP)CO (3f). The large
region of weak positive interactions can be visualized as
the green surface between the azide phenyl ring and the
catalyst’s phenyl substituents showed in Fig. 4.
Catalysts Ru(4nBuTPP)CO (3e) (4nBuTPP = dianion
of tetrakis(4-n-butylphenyl)porphyrin) and Ru(TMP)CO
(3f) (TMP = dianion of tetramesityl porphyrin) presented
a comparable lower energy barrier (18.71 kcal/mol and
18.43 kcal/mol respectively) meaning that the presence
An energy barrier of 21.87 kcal/mol was found for
the transition state involving Ru(3,5(CF3)2TPP)CO (3d)
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METAL-PORPHYRIN CATALYZED AZIRIDINATION OF α-METHYLSTYRENE: BATCH vs. FLOW PROCESS
7
Fig. 3. Transition state structures related to the interaction of catalysts 3a and 3e with azide 2a
Fig. 4. NCIPLOT analysis performed in a selected cube (see Supporting information) using geometry calculated at the B3LYP/6-
31G(d) Ru (SDD) level of theory for TSs related to catalysts 3a, 3c, 3e and 3f with azide 2a. Hydrogen atoms were omitted for clarity
Table 6. Ru–N distances of singlet C(s) and C(t) species relative to complexes 3a–3f
Entry
Catalyst
Complex C(s)
Complex C(t)
[Ru]–N distance, Å
[Ru]–N distance, Å
1
2
3
4
5
6
Ru(TPP)CO
3a
3b
3c
3d
3e
3f
1.889
1.882
1.891
1.885
1.887
1.881
1.978
1.970
1.985
1.976
1.985
1.956
Ru(OEP)CO
Ru(β-Br4TPP)CO
Ru(3,5(CF3)2TPP)CO
Ru(4nBu-TPP)CO
Ru(TMP)CO
catalyst. This highest energy barrier value was probably
due to the presence of strong electron withdrawing CF3
groups and the absence of p-staking stabilizations. This
fact was confirmed by the lower yields obtained when
this catalyst was employed in the aziridination process
involving 2a as the nitrene source (Table 3, entry 4).
The singlet → triplet spin crossing process of com-
plexes C was also investigated by DFT calculations
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D. INTRIERI ET AL.
(Table 5). As previously observed [28, 29], the high spin
isomer was more stable than the singlet one. Lower value
(4a) [41]; N-(4-nitrophenyl)-2-phenylaziridine (4b) [41]
were in agreement with those reported in literature.
of DDG° C(s)
was observed when Ru(TPP)CO was
(t)
→
used, where the difference between the singlet and triplet
state was about 4.41 kcal/mol; the highest delta value
(-7.62 kcal/mol) was obtained for Ru(TMP)CO (3f) catalyst.
Another important aspect was the increase of the
Ru–Nimido distance switching from the singlet species
of complex C(s) to the corresponding C(t) complex in
the triplet state (Table 6). In all the species investigated,
the increase of the bond length was about +0.1 Å for the
triplet state (Table 6), indicating its higher reactivity in
the formation of diradical species D, in accordance with
literature data [29].
General procedure for catalytic reactions
Method A (bach). In a typical run, the opportune
catalyst (1.20 × 10-5 mol) the opportune azide (6.00 ×
10-4 mol) and α-methylstyrene (2.50 × 10-3 mol) were
added to benzene (25 mL) in a Schlenk flask. The
reaction solution was refluxed by using a preheated
oil bath. The consumption of the azide was monitored
by IR spectroscopy measuring the characteristic azide
absorbance in the region 2095–2130 cm-1. The reaction
was considered to be finished when the absorbance of the
latter peak was below 0.03 (using a 0.5 mm thick cell). The
solution was then concentrated to dryness and analyzed by
1H NMR with 2,4-dinitrotoluene as the internal standard.
All reaction times and products yields are reported in
Tables 1 and 2.
EXPERIMENTAL
General
Method B ( flow). In a typical experiment, syringe
A was filled with a mixture obtained dissolving 0.02 eq
(1.60 × 10-5 mol) of the opportune catalyst in 2.0 mL of
the desired α-methylstyrene in order to have 0.008 M
concentration of catalyst. The mixture was sonicated for
10 min and heated until a complete dissolution of the
catalyst. Syringe B was filled with a mixture obtained
dissolving 1.0 eq of the desired azide (8.00 × 10-4 mol)
and 0.075 eq of biphenyl (6.00 × 10-5 mol, 9.2 mg) as
the internal standard in 2.0 mL of α-methylstyrene
in order to have 0.4 M concentration of azide (note:
the concentrations of all reagents in the syringes were
doubled with respect to the final concentration, to achieve
the desired concentration after mixing). Syringes A and
B were connected to a syringe pump and the reagents
were pumped into PTFE mesoreactor at 120°C through
a T-junction at the flow rate of 8.333 mL/min (30 min
as residence time). One reactor volume was discarded
before starting sample collection in order to achieve
steady-state conditions. Reaction outcome was collected
into a vial cooled at -30°C and directly analyzed by GC.
Unless otherwise specified, all the batch reactions
were carried out under nitrogen atmosphere employing
standard Schlenk techniques and magnetic stirring.
Benzene and α-methylstyrene were dried over sodium
and calcium hydride, respectively and stored under
nitrogen. Ru(OEP)CO (3b) and Co(OEP) (3g) were
commercially available and used as received. Compounds
3,5(CF3)2C6H3N3 (2a) [35], 4(NO2)C6H4N3 (2b) [35],
Ru(TPP)(CO) (3a) [36], Ru(β-Br4TPP)CO (3c) [37],
Ru(3,5(CF3)2TPP)CO (3d) [38], Ru(4nBu-TPP)CO
(3e) [36], Ru(TMP)CO (3f) [36], Co(TPP) (3h) [39],
Co(TMOP) (3i) [40] were synthesized by methods
reported in literature or using minor modifications of these
methods. The purity of hydrocarbons and aryl azides
employed was checked by GC-MS or 1H NMR analyses.
All the other starting materials were commercial products
and used as received. NMR spectra were recorded at
room temperature, unless otherwise specified, on a
1
Bruker avance 300-DRX, operating at 300 MHz for H,
at 75 MHz for 13C and at 282 MHz for 19F. Chemical
shifts (ppm) are reported relative to TMS. The 1H NMR
signals of the compounds described in the following
have been attributed by COSY and NOESY techniques.
Assignments of the resonance in 13C NMR were made
using the APT pulse sequence and HSQC and HMBC
techniques. Infrared spectra were recorded on a Varian
Scimitar FTS 1000 spectrophotometer. GC analysis were
performed using Agilent 6850 single channel GC system.
Mesoreactor was prepared using PTFE tubing for HPLC
connections purchased from Supelco (1.58 mm outer
diameter, 0.58 mm inner diameter, 1.89 m length, 500 mL
effective volume) coiled in a bundle and immersed in an
oil bath. A Chemix Fusion 100 syringe pump, equipped
with one or two Hamilton gastight syringes, fed the
reactant solutions through a T-junction into the above-
mentioned PTFE tubing. The collected analytical data for
N-(3,5-bis-(trifluoromethyl)phenyl)-2-phenylaziridine
CONCLUSION
In conclusion, the addition of aryl azides to
α-methylstyrene for the synthesis of N-aryl aziridines was
successfully accomplished under batch and continuous-
flow conditions, in the presence of a ruthenium and cobalt
porphyrin-based catalysts. Generally speaking, higher
yields were observed using ruthenium-based catalysts in
a traditional batch process, but cobalt-based porphyrins
presented higher chemical efficiency under flow
conditions. Ru(TPP)CO (3a) and Ru(OEP)CO (3b) were
the best catalysts for the aziridination of α-methylstyrene
independent of the type of approach, while Co(OEP) (3g)
was the best catalyst among the cobalt-based porphyrins
investigated. This catalyst mediated the aziridination
Copyright © 2017 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2017; 21: 8–10

METAL-PORPHYRIN CATALYZED AZIRIDINATION OF α-METHYLSTYRENE: BATCH vs. FLOW PROCESS
9
process under solvent-free flow conditions in only 30 min
at 120°C using a 500 mL PTFE microreactor.
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A preliminary DFT investigation about the catalytic
effect of the substituent on the porphyrin ring in the
aziridination process was also performed. This DFT
study highlighted that the presence of electron donating
substituentsontheporphyrinringfacilitatedtheformation
of the mono-imido [Ru](NAr)CO complex by dismissal
of a N2 molecule from the starting azide. In addition,
electron rich ruthenium complexes showed also a higher
stabilized triplet ground state which is considered the real
active species in the aziridination process.
Acknowledgements
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D.I and S. R. thanks Università degli Studi di Milano
for post-doc fellowships.
Supporting information
Supplementary material is available free of charge
via the Internet at http://www.worldscinet.com/jpp/jpp.
shtml.
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