Light-Induced Regiospecific Bromination of meso-Tetra(3,5-di-tert-butylphenyl)Porphyrin on 2,12 β-Pyrrolic Positions

Article abstract of DOI:10.1021/acs.joc.5b00367

The antipodal introduction of two bromine atoms on the 2,12 β-pyrrolic position of 5,10,15,20-tetra(3,5-di-tert-butylphenyl)porphyrin was successfully achieved by a light-induced reaction of the substrate with excess NBS. Complexation with Ni^II of the major regioisomer led to good quality crystals, suitable for X-ray structure determination with unprecedented probability levels. The regiospecific character of the synthetic procedure and the exactness of the bromine atom position assignment were thus confirmed, suggesting an unexpected electrophilic aromatic substitution pathway rather than a free-radical halogenation process. A QTAIM topological analysis on the DFT-optimized wave function of the monosubstituted free-base porphyrin intermediate carrying a bromine atom in C2 β-pyrrolic position confirmed the largest negative charge for the C12 carbon atom in antipodal position, in agreement with the proposed electrophilic aromatic substitution mechanism. (Figure Presented).

Full text of DOI:10.1021/acs.joc.5b00367

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Article
Light-Induced Regiospecific Bromination of meso-Tetra(3,5-
Di-tert-butylphenyl)Porphyrin on 2,12 beta-Pyrrolic Positions
Gabriele Di Carlo, Alessio Orbelli Biroli, Francesca Tessore, Silvia
Rizzato, Alessandra Forni, Giulia Magnano, and Maddalena Pizzotti
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 20 Apr 2015
Downloaded from http://pubs.acs.org on April 25, 2015
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LightꢀInduced Regiospecific Bromination of mesoꢀ
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Tetra(3,5ꢀDiꢀtertꢀbutylphenyl)Porphyrin on 2,12
βꢀ
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Pyrrolic Positions
Gabriele Di Carlo,*,† Alessio Orbelli Biroli,‡ Francesca Tessore,† Silvia Rizzato,† Alessandra
Forni,†,‡ Giulia Magnano† and Maddalena Pizzotti†
† Department of Chemistry, University of Milan, Via C. Golgi 19, 20133 Milano, Italy
‡ Institute of Molecular Sciences and Technologies of CNR (ISTMꢀCNR), Via Golgi 33, Iꢀ20133
Milano, Italy
Eꢀmail: gabriele.dicarlo@unimi.it
GRAPHICAL ABSTRACT
A Schematic Representation of the LightꢀInduced Regiospecific Functionalization of mesoꢀ
Tetra(3,5ꢀDiꢀtertꢀbutylphenyl)Porphyrinic Core by NBSꢀmediated Bromination.
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KEYWORDS: Porphyrins, Regioselective Bromination, XꢀRay Structure Determination, DFT
Calculations
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ABSTRACT
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The antipodal introduction of two bromine atoms on 2,12 βꢀpyrrolic position of 5,10,15,20ꢀ
tetra(3,5ꢀdiꢀtertꢀbutylphenyl)porphyrin was successfully achieved by a lightꢀinduced reaction of the
substrate with excess NBS. Complexation with NiII of the major regioisomer led to good quality
crystals, suitable for Xꢀray structure determination with unprecedented probability levels. The
regiospecific character of the synthetic procedure and the exactness of the bromine atom position
assignment were thus confirmed, suggesting also an unexpected electrophilic aromatic substitution
pathway rather than a freeꢀradical halogenation process. A QTAIM topological analysis on the DFT
optimized wavefunction of the monoꢀsubstituted freeꢀbase porphyrin intermediate carrying a
bromine atom in C2 βꢀpyrrolic position confirmed the largest negative charge for the C12 carbon
atom in antipodal position, in agreement with the proposed electrophilic aromatic substitution
mechanism.
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INTRODUCTION
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Porphyrins are one of the most widely investigated classes of molecules in chemistry,1 because they
are featured by high chemical stability, interesting optical and photophysical properties and
catalytic activities, all of which are being used in a wide range of research fields such as medicine,2
biology,3 catalysis,4 optoelectronics5ꢀ7 and green energy engineering.8ꢀ10 Porphyrins can also be
subjected to a modulation of their chemical structure resulting in rational control of their electronic
properties. In particular, chemical functionalization of porphyrinic core via a bromination strategy11
followed by crossꢀcoupling reactions12 or nucleophylic aromatic substitutions13,14 appears to be
beneficial in tuning the properties of macrocyclic systems in accordance with the structural
requirements necessary for a specific application. In fact it was recently reported by some of us that
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the properties of
β
ꢀfunctionalized ZnIIꢀporphyrinates are strongly influenced by introducing πꢀ
delocalized systems to the macrocyclic core.5,15 These substituents directly linked on pyrrolic
positions exert strong steric and electronic effects on the porphyrinic rings16 resulting in a dramatic
alteration of their optical, electrochemical and spectroelectrochemical properties.17 For these
reasons brominated porphyrinic intermediates are considered extremely important buildingꢀblocks
to synthesize more complex and extended structures and thus numerous synthetic approaches have
been proposed in order to selectively functionalize the macrocyclic ring on its different positions.11
Owing to the large number of delocalized πꢀelectrons, the porphyrinic core is highly sensitive to
electrophilic aromatic substitution reactions which can occur on two different receptive positions.
The carbon atoms at the meso positions, consisting of four methenyl bridges on the porphyrinic
core, exhibit excellent reactivity to the substitution of a hydrogen with a bromine atom, so that their
functionalization occurs with high yields under relatively mild conditions.18,19 On the contrary
βꢀ
positions, comprising the eight carbon atoms of the four pyrrolic rings, are less responsive to the
bromination reaction requiring stricter settings.20,21 These severe reaction conditions strongly
influence the substitution degree of the porphyrinic core which is difficult to control. Hence a
mixture of polyꢀbrominated derivatives and several regioisomers are typically obtained by various
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β
ꢀbromination procedures.11 Furthermore hard purification steps of the reaction mixture are
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required inducing, in turn, a decrease of the overall yield of a single specifically brominated species.
Since the 70s, several bromination procedures have been investigated in order to obtain various
β
ꢀ
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functionalized tetraarylporphyrinic structures, in particular via synthetic pathways involving Nꢀ
Bromosuccinimide (NBS). Among all of the reported approaches the method first proposed by
Callot,20,21 which requires to reflux a solution of tetraphenylporphyrin (TPP) in CHCl3 with
appropriate equivalents of NBS, is still the most commonly used. Thanks to this approach, it has
been possible to functionalize the porphyrinic core with a range of bromine atoms from one to
eight. Numerous authors have employed this procedure to brominate either TPP or other different
tetraarylporphyrins.22ꢀ24 Subsequently, other NBS mediated bromination procedures12,25 were
proposed to attain polyꢀfunctionalized porphyrins,26ꢀ28 however only in a few cases the reaction
mechanism was investigated in detail. Consequently, factors and reaction conditions which drive
the regiochemistry of these substitutions,13 especially when various bromine atoms should be
introduced in specific positions of the porphyrinic ring, are still quite unknown.
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A particularly unclear topic remains the partial bromination of the antipodal positions, indeed
several attempts to selectively introduce only two bromine atoms on opposite pyrrolic residues in a
well defined arrangement failed. Bhyrappa et al.29 have achieved the antipodal introduction of two
bromine atoms on free base TPP by controlling the concentration of NBS working at room
temperature obtaining a mixture of 2,12/2,13/2,3 dibromo regioisomers. An alternative bromination
procedure of freeꢀbase nonꢀplanar porphyrins involving two equivalents of NBS in refluxing
chloroform was reported by Senge at al.30 to give a small portion of 2,13ꢀdibromo isomer in a pure
form after repeated purification steps of the complex reaction mixture.
Despite the difficulties in obtaining porphyrinic rings specifically dibrominated on the antipodal
pyrrolic positions with significant yields and in pure forms, these structures have emerged as
fundamental precursors for the synthesis of specific asymmetric pushꢀpull systems.10 These latter, in
fact, showing highly defined architectures, play an extremely important role as chromophores both
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in nonꢀlinear optics (NLO)5,6 and in Dye Sensitized Solar Cell (DSSC)10 applications. The
regiospecific functionalization of opposite pyrrolic units is thus considered the focal step to obtain
the key buildingꢀblocks for the synthesis of attractive pushꢀpull porphyrinic systems. Therefore it
has become of great interest to develop a facile and effective synthetic procedure to successfully
introduce two bromine atoms on specific antipodal positions thus reducing the formation of
regioisomers and increasing the overall synthetic yield of such specific porphyrinic systems.
As the electronic distribution of the πꢀdelocalized porphyrinic core is strongly influenced by the
four meso aryl substituents, which then affect the pyrrolic substitution degree and consequently the
functionalization yields, it is unrealistic to design a general bromination procedure suitable for all
tetraarylporphyrinic systems. For these reason, in this work, we have focused our attention on a
specific substrate consisting of the freeꢀbase 5,10,15,20ꢀtetra(3,5ꢀdiꢀtert-butylphenyl) porphyrinic
core 1 and on its ZnII ꢀcomplex Zn-1 (Scheme 1).
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Scheme 1. Schematic NBSꢀmediated bromination of the freeꢀbase porphyrin (1) and the ZnIIꢀ
porphyrinate (Zn-1) on βꢀpyrrolic positions. The positions of substituents in dibrominated (3 and
Zn-3) and in polybrominated (4 and Zn-4) porphyrinic structures depend on bromination
conditions.
With the aim to compare the efficiency and the selectivity of various bromination procedures on
substrates 1 and Zn-1, the relative amounts of monobromo substituted porphyrins (2 and Zn-2),
dibromo substituted porphyrins (3 and Zn-3) and polybrominated derivatives will be also reported
(Table 1).
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Table 1. Set of Various Synthetic Attempts; “X” Is the Relative Amount of Products in the Crude of
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Reaction.
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Reaction Conditions
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a20,21
b31
c32
d33
e12
f10,17
g
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1.7
1.1
1.1
1.7
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1.8
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2.1
2.2
2.2
2.2
CHCl3; 1h reflux
•
•
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Py; CHCl3, 1h r.t.
XX
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CH2Cl2/CH3OH; 10 min reflux
CHCl3; 18h reflux
CH3OH; 1h reflux
CCl4; 2h reflux
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XXX
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XXX
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XXX
XXX
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XXX
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CCl4; 2h reflux
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-
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CCl4; 200W lamp 4h
CH2Cl2; 200W lamp 4h
CH2Cl2; 200W lamp 4h
CH2Cl2; 4h reflux
h
X
X
i
X
-
j
•
-
X
k
X
XX
•
amixtures of regioisomers
Furthermore, the rational optimization of the reaction conditions has allowed us to develop a
regiospecific synthetic procedure to unquestionably obtain the 2,12ꢀdibromo substituted
regioisomer 3 (Scheme 2).
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Scheme 2. Schematic representation of the tautomeric equilibrium of the 18ꢀπꢀannulene system in
the monobromo intermediate 2 and the assignment variation of the bromine substituent according to
the different ways of fixing the inner hydrogens. Regiospecific synthesis of the freeꢀbase 2,12ꢀ
dibromo substituted porphyrin (3) and its NiIIꢀporphyrinate (Ni-3).
In particular, this specific antipodal pyrrolic functionalization occurred with good yields on the freeꢀ
base porphyrinic core by a lightꢀinduced reaction with Nꢀbromosuccinimide (NBS) in
dichloromethane. The complexation of the regioisomeric product gave the NiII complex Ni-3
(Scheme 2) in pure form providing good quality crystals for Xꢀray structure determination
(Figure 1) which confirmed the accuracy of the substituents assignment and the high
regiospecificity of the proposed synthetic procedure. Crystallographic details of the data collection
and refinement parameters (Table S1) as well as selected bond lengths [Å] and angles [°] for
compound Ni-3 (Table S2) are reported in the Supporting Information.
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Figure 1. A view of the molecular structure of Ni-3 with the atomꢀnumbering scheme. Thermal
ellipsoids are represented at the 50% probability level. Hydrogen atoms and disorder are omitted for
clarity. Only one set of rotationally disordered bromine substituents is shown.
The selective introduction of bromine atoms on the specific 2,12
βꢀpyrrolic positions has also
suggested that this lightꢀinduced bromination procedure occurred by an unexpected electrophilic
aromatic substitution pathway rather than via a freeꢀradical halogenation process. The substitution
mechanism has been rationalized by means of quantumꢀmechanical calculations on both
monobromo derivative
2 and its metal complex Zn-2 (Table 2), in vacuo and in solvent, aimed at
determining the net atomic charges of the pyrrolic carbons after introduction of the first bromine
atom on a pyrrolic position of the porphyrinic ring. These calculations allowed us to determine the
electronic effect of the halogen substituent on the remaining pyrrolic carbons, thus predicting the
more reactive sites for electrophilic substitution.
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Table 2. M06/6ꢀ311G(d) Integrated Net Charges q (e) of the Atomic Basins of MonoꢀBrominated
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FreeꢀBase (
QTAIM Partitioning
2), in vacuo and CH2Cl2, and its Zn Complex (Zn-2) in vacuo and CCl4, Computed by
Atom
FreeꢀBase (
2
)
ZnIIꢀComplex (Zn
ꢀ2)
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vacuum
ꢀ0.0421
ꢀ0.0477
ꢀ0.0482
ꢀ0.0776
ꢀ0.0769
ꢀ0.0487
ꢀ0.0461
CH2Cl2
ꢀ0.0464
ꢀ0.0482
ꢀ0.0489
ꢀ0.0817
ꢀ0.0813
ꢀ0.0496
ꢀ0.0486
vacuum
ꢀ0.0345
ꢀ0.0654
ꢀ0.0656
ꢀ0.0678
ꢀ0.0659
ꢀ0.0659
ꢀ0.0633
CCl4
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C3
ꢀ0.0379
ꢀ0.0693
ꢀ0.0692
ꢀ0.0714
ꢀ0.0698
ꢀ0.0699
ꢀ0.0678
C7
C8
C12
C13
C17
C18
RESULTS AND DISCUSSION
In the last decades several efforts were devoted to optimize the conditions to regiospecifically
brominate the pyrrolic rings of porphyrinic core.11ꢀ13,34 Up to now the reported synthetic procedures
led mainly to complex mixtures of variously substituted porphyrins providing by purification only
crystals with disordered structures wherein bromine atoms were arranged in several
positions with different probabilities.29,30
βꢀpyrrolic
Crossley et al.35 first observed the regiospecific introduction of 4 bromine atoms at the antipodal
positions of a tetraarylporphyrin. The driving force of such a selective functionalization was
suggested to be due to the degenerate aromatic systems of the porphyrinic core. The aromatic
delocalization, defined by a 18ꢀπꢀannulene system with two isolated double bonds on the
porphyrinic periphery, involved two distinct tautomeric forms (Scheme 2). When a substituent was
introduced in a βꢀpyrrolic position, the aromatic delocalization pathway was altered shifting the
equilibrium to the tautomeric form with a localized double bond arranged on the pyrrolic ring
opposite to that bearing the substituent. Hence a more susceptible site to electrophilic attach
resulted on the antipodal pyrrolic position compared to the 18ꢀπꢀannulene system with a more
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prominent aromatic character. Subsequently, Crossley et al.13 have also shown that the reaction of
freeꢀbase porphyrins with 4.3 equivalents of NBS in boiling ethanolꢀfree chloroform afforded the
7,8,17,18 tetrabromo substituted porphyrin rather than the misassigned 2,7,12,17 tetrabromo isomer
as previously proposed by Callot.20,21 Moreover, Smith et al.36 have described a further attractive
synthetic approach to drive a dibromination of porphyrins regiospecifically on C2 and C3 pyrrolic
positions. A suitable electronꢀwithdrawing moiety, such as a nitro group, previously introduced in a
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β
ꢀpyrrolic site, was able to impose the electrophilic attack at both carbons of the antipodal pyrrolic
ring.
Here, we focused our attention on the specific porphyrinic core
1 consisting of four 3,5ꢀdiꢀtertꢀ
butylphenyl units directly linked on 5,10,15,20 mesoꢀpositions (Scheme 1). This substrate was
previously selected, by some of us, as a suitable precursor to synthesize various ꢀsubstituted
β
porphyrinic ZnII complexes as promising sensitizers to assemble highly performing DSSCs.10,15,37
The bulky aryl substituents were evidenced to confer a great sterical hindrance to the dye structures
thus suppressing the undesired aggregation among porphyrinic systems and simultaneously
inducing excellent passivation of the TiO2 photoanode37 thanks to its intrinsic shielding character.
With the aim to optimize the selective
βꢀpyrrolic functionalization of the porphyrinic core on
specific antipodal sites, we have performed several NBSꢀmediated bromination procedures both on
and on its ZnIIꢀcomplex Zn-1. An overview of the tested methods is
schematically reported in Table 1. The entries a-f10,12,17,20,21,31ꢀ33 have already been investigated for
freeꢀbase porphyrin
1
TPP or similar porphyrinic molecules, thus, by using
be noticed in the reaction results when compared to those earlier reported. Finally, the conditions of
procedures g-k have been rationally optimized specifically for our substrates, and Zn-1, in order
to improve both regioselectivity and reaction yield. It was observed that a-e bromination procedures
yielded a complex mixture of products consisting of the unreacted porphyrin ( or Zn-1), the monoꢀ
bromo derivative ( or Zn-2), dibrominated regioisomers ( or Zn-3) and the polyꢀfunctionalized
1 and Zn-1 as substrates, some differences can
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derivatives (
4
or Zn-4), resulting in a hard purification of the crude. The monoꢀfunctionalization of
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the core was observed to successfully occur in good yield by optimizing the procedure proposed by
D’Souza.17 In particular a solution of the ZnIIꢀporphyrinate Zn-1 in CCl4 was refluxed in presence
of a slight excess of NBS (1.1 equivalents), as previously reported by some of us,10 while 1.8
equivalents were necessary to give the diꢀbrominated ZnIIꢀporphyrinate Zn-3. This latter was
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obtained with good yield (60%) as major component of reaction mixture following the procedure
f
but we failed in the first attempts to discriminate which of the dibrominated regioisomers are
mainly formed as previously suggested.10 Only the slow evaporation at low temperature of a THF
solution of Zn-3 has allowed us to obtain crystals good enough for an Xꢀray crystallographic
structure determination (see Figure S1 in the Supporting Information). The crystallographic
investigation has revealed the presence of the 2,13 diꢀbromo derivative as the major component in
a crystal containing at least 3 diꢀsubstituted regioisomers. In fact, the Zn-3 Xꢀray structure has
shown a disorder similar to those previously reported,29,30 thus it was necessary to refine the crystal
structure by using a siteꢀoccupancy disorder model. The bromine substituents were located in the
Fourier difference map and were refined with free occupancy variables and fixed Bꢀfactors. The
similarity in the resulting occupancies has allowed the identification of the three regioisomers
although problems related to poor quality of the crystal and the low intensity of the diffraction
pattern have not led to satisfactory R values. Despite these limitations the occupancy of the 2,13
disubstituted isomer has been found to be 50%, whereas the occupancies of the 2,7 and 2,3 isomers
have been 33% and 17% respectively. These findings have suggested a reduced selectivity of the
bromination of a metalloꢀporphyrinate that could be rationalized by the loss of localized doubleꢀ
bond character in the macrocyclic π system after metallation of the porphyrinic core.13 Nevertheless
it is noteworthy that no unreacted product has been recovered by bromination of Zn-1 using
f and j
procedures suggesting an increased reaction yield when the reaction takes place on the ZnIIꢀ
porphyrinate, with the exception of procedure
e which resulted ineffective due to the low solubility
of the porphyrinate in methanol. The observations reported in Table 1 have also suggested that at
least 1.8 equivalents of NBS (entries f-k) are necessary to obtain appreciable amount of β diꢀ
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brominated porphyrins. Moreover, in order to reduce the formation of polyꢀbrominated products
and to improve the regiospecific functionalization of the pyrrolic rings of porphyrinic core, mild
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reaction conditions are mandatory (entries h-j). Finally, the synthetic procedure
i has been
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appointed as an effective route to unquestionably provide a specific antipodal diꢀbromo
regioisomer. In this procedure the lightꢀinduced bromination approach has specifically provided the
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pure 2,12 diꢀbromo isomer
ditertbutylphenyl) porphyrin
3
1
with 42% yield starting from the freeꢀbase 5,10,15,20 tetra(3,5ꢀ
as summarized in Scheme 2. This regiospecific functionalization
process takes place in the presence of 2.2 equivalents NBS by irradiating the reaction mixture with
a 200W lamp which maintains a slight reflux in dichloromethane. Hence, with the aim to validate
the positive effect of the light irradiation on regioselectivity, we have also performed the
bromination step of the freeꢀbase porphyrin
1 by refluxing the reaction vessel in dark conditions
(entry
k, Table 1). This latter method has provided a complex mixture of regioisomers hard to
purify, similar to that achieved by Callot procedure,20,21 thus confirming our assumptions.
The β disubstituted porphyrinic regioisomer
3, obtained as major component by the lightꢀinduced
procedure , after chromatographic purification has successfully reacted overnight, in a 1,2ꢀ
i
dichloroethane refluxing solution, with Nickel(II) acetylacetonate (Ni(acac)2) giving quantitatively
the pure NiIIꢀporphyrinate Ni-3, as shown in Scheme 2. This latter step has given crystals of very
good quality thus allowing an Xꢀray structure determination with unprecedented probability levels.
The Ni-3 molecular structure, reported in Figure 1, presents a bromine distribution and a rotational
disorder very similar to those reported for the molecular structure of 2,12ꢀdibromoꢀ5,10,15,20ꢀ
tetraphenylphorphyrin,30 wherein half of the molecule, and therefore only one bromine, was present
in the asymmetric unit. The second antipodal substituent was generated by symmetry leading to one
specific regioisomer. Actually, in that structure, the bromine atoms were disordered over three
different positions, refined with different occupancies, generating a clear and well defined rotational
disorder. On the contrary, in the Ni-3 crystal structure there is only one crystallographically
independent molecule which shows four disordered bromine atoms in 2,3 and 12,13 positions.
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However, the rotational disorder is well resolved because it is limited to the two specific positions
and the high quality of the data has allowed us to couple the bromine atoms in 2,12 antipodal
positions. Thus the nature and the purity of Ni-3 regioisomer, and consequently of its freeꢀbase
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precursor
3, have been confirmed.
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It is noteworthy that a diꢀbromo derivative, very similar to the porphyrin
3
, was previously
identified by Crossley et al.13,35 as a 7,17 rather than a 2,12 disubstituted regioisomer. This
particular attribution was ascribed to the introduction of bromine atoms on β pyrrolic carbons with
the inner hydrogens at the porphyrinic ring fixed in Nꢀ21 and Nꢀ23 positions (Scheme 2) thus
imposing the character of double bonds in ꢀ7,8 and ꢀ17,18. On the other hand, metalꢀcomplexation
reverts the attribution to the 2,12ꢀdibromo regioisomer since no tautomeric forms are allowed due to
the lack of inner hydrogens. Such effect on the assignment of the substituents position could make
the comparison of the freeꢀbase porphyrinic derivatives with their metal complex forms rather
unclear. Hence, for a better comprehension of our results, we have arbitrarily assigned the
substituents position starting from C2 even for the freeꢀbase porphyrin
base porphyrin will be referred as to the 2,12 dibrominated regioisomer (Table 2) rather than to its
7,17 tautomeric form.
3. Consequently, the freeꢀ
3
With the aim to gain deeper insight about geometrical characteristics of the 2,12 dibrominated NiII ꢀ
porphyrinate, the distances among atoms within the porphyrinic core and the resulting distortion of
structure were further investigated. The Ni(II) metal center adopts a quasiꢀideal square planar
coordination geometry with the NꢀNiꢀN angles near 90° (89.33ꢀ 90.74°) and a maximum deviation
of 0.003 Å from the NiN4 mean plane. The average NiꢀN distance of 1.909 Å is quite similar to that
found in other analogous complexes38 though the bond lengths in the case of the two nitrogen of the
brominated pyrrolic rings result slightly longer (1.898ꢀ1.896 Å; 1.911ꢀ1.932 Å). This is due
essentially to the distortion of the porphyrinic core that results in a different transannular distance
for the two N· ·N couples. Thus the macrocyclic hole results stretched in the direction of the two
substituted rings as frequently observed in the distortion pattern of metal complexed
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porphyrins.30,36,39 The significant distortion of the porphyrin core can be described as a mixing of
saddle and ruffle distortion modes with a maximum displacements from the 24ꢀcore atoms mean
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plane of 0.64 and 0.40 Å for the mesoꢀcarbons (ruffleꢀshaped distortion) and βꢀpyrrolic positions
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(saddleꢀshaped distortion) respectively. The noteworthy contribution of the ruffling distortion to the
macrocycle deformation is stressed by the value of the dihedral angles between the planes of the
opposite pyrrolic rings (38.9° and 37.6°). Instead, the dihedral angles between the phenyl rings and
the mean plane formed by the 24ꢀatoms core, lie in the range 73.5°ꢀ 89.1° that suggest only weak
steric interactions between the phenyl rings and the adjacent antipodal bromine substituents.
With the aim to rationalize the impressive regiospecificity obtained by the lightꢀinduced NBSꢀ
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mediated bromination of
1 we were interested in figuring out the mechanism which drives the
introduction of the two bromine atoms on 2,12 pyrrolic positions of the porphyrinic core. As
previously reported40 and now confirmed by our results, the freeꢀbase porphyrinic ring
1
results to
be less reactive to the bromine aromatic substitutions than the ZnIIꢀporphyrinate Zn-1, thus the light
irradiation has been initially employed to improve the reaction rates. At first this approach was
reasonably expected to promote a radical pathway involving a homolytic bond cleavage of NBS.
With the light irradiation, instead, the NBSꢀmediated bromination has specifically provided the 2,12
diꢀbromo regioisomer
3
as major product, the monoꢀbromo derivative
2
as minor component and
). Even if it is
only small traces of other diꢀbromo regioisomers and polyꢀbrominated derivatives (
4
known that NBS can react both by radical mechanisms in the case of nonꢀdelocalized doubleꢀ
bonds41 or by electrophilic aromatic substitution in polar42 and in non polar solvents,43 the observed
remarkable regiospecificity by a lightꢀinduced bromination was unexpected. However similar
findings were earlier reported by Gruter et al.44 who evidenced that the nuclear bromination of
anisole took place via an electrophilic aromatic substitution mechanism under irradiation
conditions.
Consequently an inꢀdepth theoretical investigation has been performed to support and rationalize
the electrophilic aromatic substitution process. The results of a QTAIM topological analysis on the
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charge density distribution of the freeꢀbase monoꢀbrominated porphyrin 2, as determined by M06/6ꢀ
4
5
6
7
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311G(d) DFT calculations both in vacuo and in the same solvent used for the synthesis (CH2Cl2),
are summarized in Table 2. In this Table, we report the net atomic charges obtained by integration
over the volume of atomic basins as defined within QTAIM. It can be noticed that the carbon atoms
C12 and C13, in antipodal position with respect to the pyrrolic unit bearing the bromine atom, show
the largest negative charges, while the carbon atom C3, adjacent to the bromine substituted carbon,
is the less negative one. By comparing the net charges on C12 and C13 very small differences can
be observed, with the former showing slightly more negative charge than the latter. This trend is
confirmed to be the same both in vacuo and in CH2Cl2 solvent and also by varying the
computational methodology (see Table S3), thus suggesting a slight preference of an electrophilic
aromatic substitution on C12 position rather than on C13, as experimentally observed.
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In order to better understand the influence of the metal complexation on the electrophilicity of
porphyrinic core, the atomic net charges on the pyrrolic carbons of the porphyrinic intermediate Zn-
2
have been also determined in vacuo and in CCl4, the solvent used for the synthesis (see Table 2).
A slightly more negative charge was obtained for the C12 carbon atom on the opposite side of
pyrrolic ring bearing the bromine substituent. Nevertheless in this case the charge values are much
more homogeneous within the different carbon atoms, except for the C3 position which shows a
significantly less negative net charge. Therefore the computational investigation has evidenced that
(i) the electrophilic aromatic substitution is prevented on C3 position, as experimentally observed,
almost certainly due to the inductive effect of the bromine atom linked to the C2 carbon; (ii) the
selective introduction of a second bromine atom on a specific carbon atom of the opposite pyrrolic
ring appears to be much more pronounced on the mono functionalized freeꢀbase porphyrin
2 rather
than on its ZnIIꢀcomplex counterpart Zn-2, confirming the loss of regioselectivity in the
bromination reaction after metal complexation step of the porphyrinic core; and (iii) our QTAIM
findings are consistent with an electrophilic aromatic substitution mechanism which drives the
introduction of the second bromine atom specifically on the pyrrolic sites having the most
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electronegative character. On the other hand, calculations on all the possible cationic intermediates
approximating the transition state from the monoꢀ to the diꢀbrominated freeꢀbase derivatives
provided essentially, in the more stable configuration, the same energies for the species leading to
the 2,12 and the 2,13 regioisomers. The former emerged to be more stable than the latter for less
than 0.1 kcal/mol, and slightly higher energies (up to 1.9 kcal/mol) were obtained for the other
possible intermediates (see SI for details). Despite a free radical halogenation mechanism cannot
therefore be ruled out entirely, all the experimental evidences suggested an electrophilic aromatic
substitution process.
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CONCLUSIONS
In this work we have tested and compared some of the most used NBSꢀmediated bromination
procedures on both the freeꢀbase 5,10,15,20 tetra(3,5ꢀditertbutylphenyl) porphyrin
1
and on its ZnIIꢀ
complex Zn-1. Furthermore some alternative synthetic procedures have been also reported for the
same substrates. We have found that the lightꢀinduced bromination of 1, under rather controlled
conditions, occurs regiospecifically on the 2,12 antipodal positions giving the 2,12 dibrominated
porphyrin
3
as major component with remarkable reaction yields. The subsequent complexation
step of
3
with Ni(acac)2 has provided suitable crystals of the NiIIꢀporphyrinate Ni-3 for an inꢀdepth
crystallographic investigation. The 2,12 dibromo regioisomer, thus obtained, has been identified
with an unprecedented confidence degree due to the impressive probability levels of the Xꢀray
analysis confirming the high regiospecificity of the lightꢀinduced bromination of the porphyrinic
core by NBS. Interestingly some differences have been observed in the behaviour of the Zn-1
complex. In this latter case the NBSꢀmediated bromination occurs rapidly and with high yields but
with a limited regioselectivity, although the 2,13 disubstituted regioisomer was evidenced as the
major component.45
Finally, a computational investigation has been performed to gain mechanistic information about
NBSꢀmediated bromination of porphyrinic substrates and to support the findings concerning the
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regiospecificity of such reaction. In particular, after introducing a first bromine atom in C2 position,
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significant differences between the freeꢀbase porphyrin
evidenced as far as the relative values of negative net charges on the pyrrolic carbons were
2
and its ZnII complex Zn-2 have been
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concerned. Such charges have been found to be quite different in the freeꢀbase porphyrin
2 and
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rather homogenous in ZnIIꢀporphyrinate Zn-2, except for the C3 position adjacent to bromine
substituted carbon atom. In the case of 2, the higher negative charges have been located respectively
on carbons in antipodal position, in agreement with the observed significant reactivity of these
positions to electrophilic substitution reaction. Conversely, in the case of Zn-2, the reduced
differences in the net charges of the βꢀpyrrolic carbons fully support the limited regioselectivity
observed for the complexed porhpyrin. This different behaviour is rationally explained by the loss
of localized doubleꢀbond character of the antipodal pyrrolic ring, as previously suggested by
Crossley at al.13 for metalꢀcomplexed porphyrins.
In conclusion, the reported results have shed some more light on the dibromination reaction of the
porphyrinic ring. They have also shown that the regiospecific introduction of two bromine atoms on
the opposite pyrrolic rings is in good agreement with an electrophilic aromatic substitution
mechanism, although further mechanistic studies would be needed to confirm this hypothesis.
EXPERIMENTAL SECTION
Materials
All reagents and solvents used in the synthesis were purchased by Sigma Aldrich and used as
received, except NꢀBromosuccinimide (freshly crystallized in boiling water). The Zn-2 and Zn-3
porphyrins were synthesized as reported elsewhere10 and a schematic synthetic pathway is
illustrated in scheme 1. Silica gel for gravimetric chromatography (Geduran Si 60, 63ꢀ200 ꢁm) and
for flash chromatography (Geduran Si 60, 40ꢀ63 ꢁm) were purchased by Merck. Glassware was
flameꢀdried under vacuum before use when necessary. A 200 W commercial tungsten light bulb
was adopted for the light source.
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1H NMR spectra were recorded at 25°C in CDCl3 as solvent with addition, when necessary, of a
drop of pyridineꢀd5 or in THFꢀd8 (Cambridge Isotope Laboratories, Inc.). Mass spectra were
obtained by a magnetic mass spectrometer with a LSIMS ionic source.
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Synthesis of 2,12-dibromo-5,10,15,20-tetra(3,5-di-tert-butylphenyl)porphyrin (3)
In a 250 mL twoꢀneck roundꢀbottom flask a solution of porphyrin
1 (200 mg, 0.19 mmol) in CH2Cl2
(75 mL) and NBS (73 mg, 0.41 mmol) were introduced. Afterwards, a light source consisted of a
200W lamp, was placed at about 10 cm distance from the reaction vessel so that a slightly reflux
was maintained. The mixture was allowed to react and after 4 hours the complete disappearance of
the starting porphyrin was evidenced by TLC (CH2Cl2/nꢀhexane = 2/8). The reaction was quenched
by adding acetone and, after removal of the solvent in vacuo, the crude was purified by flash
chromatography (SiO2; column diameter = 3.5 cm; column height = 30 cm; CH2Cl2/nꢀhexane =
12/88). The major product, consisting of diꢀbromo porphyrin
3
, was collected in the first eluted
obtained by
fraction as a deep pink powder (96 mg, 42% yield) whilst the minor product
2
incomplete bromination of the porphyrinic core was contained in the second eluted fraction.
1HꢀNMR (400 MHz, CDCl3, 25°C) δ, ppm 8.95ꢀ8.88 (m, 6H), 8.05 (s, 4H), 7.95 (s, 4H), 7.83 (s,
2H), 7.82 (s, 2H), 1.55 (s, 36H), 1.53 (s, 36H), ꢀ2.89 (s, 2H) . MSꢀFAB(+): m/z: 1220 [M+H+]+.
Anal. Calcd for C76H92Br2N4: C, 74.74; H, 7.59; N, 4.59. Found: C, 75.01; H, 7.57; N, 4.60.
Synthesis of 2,12-dibromo-5,10,15,20-tetra(3,5-di-tert-butylphenyl)porphyrinate NiII (Ni-3)
In a twoꢀneck roundꢀbottom flask a solution of
3 (20 mg, 0.016 mmol) in 1,2ꢀdichloroethane (5 mL)
was slightly warmed and, whilst stirring, then Ni(acac)2 (12 mg, 0.047 mmol) was added
portionwise. The resulting mixture was refluxed overnight and after removal of the solvent in
vacuo, the pure product Ni-3 was obtained as a reddish powder in quantitative yield by washing and
filtering the crude with H2O milliQ.
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1HꢀNMR (400 MHz, CDCl3, 25°C) δ, ppm 8.91ꢀ8.87 (m, 2H) 8.82 (s, 2H), 8.73ꢀ8.71 (m, 2H), 7.81
(s, 4H), 7.72 (s, 2H), 7.68 (s, 2H), 7.66 (s, 4H), 1.47 (s, 36H), 1.44 (s, 36H). MSꢀFAB(+): m/z:
1278 [M+H+]+. Anal. Calcd for C76H90Br2N4Ni: C, 71.42; H, 7.10; N, 4.38. Found: C, 71.68; H,
7.07; N, 4.40.
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ACKNOWLEDGMENT
MP and GDC thank the “Fondazione Tronchetti Provera” for financial support. The authors thank
Prof. Renato Ugo for the fundamental advices and the useful discussions.
Supporting Information: Experimental procedures for Xꢀray Crystal Structure Determination and
Computational Details are described in the Supporting Information. Crystallographic details of the
data collection and refinement parameters for Ni-3 (Table S1), Xꢀray molecular structure of
compound Zn-3 (Figure S1), Hypothetical cationic intermediates (Figure S2) Integrated Net
Charges of
2 and Zn2 computed by QTAIM Partitioning (Table S3), Selected bond lengths and
angles for compound Ni-3 measured (Table S2) and computed (Table S4) as well as M06/6ꢀ
311G(d) relative energies (kcal/mol) of the hypothetical cationic intermediates (Table S5) and
Cartesian coordinates of the modelled compounds (Table S6) are reported on Supporting
Information. This material is available free of charge via the Internet at http://pubs.acs.org.
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also to the pushꢀpull dyes produced by subsequent reactions of the b dibromo ZnIIꢀporphyrinate, the
2,13 isomeric structure should be assigned.
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