Bromination of tetrapyrrolic scaffolds: A sustainable approach

Article abstract of DOI:10.1039/c9nj02503k

A sustainable procedure developed for the bromination of organic substrates, such as olefins and small aromatic rings, has been applied to porphyrin derivatives. The synthetic method, based on a V(v) or Mo(vi) catalyzed reaction, occurs in a two-phase med

Full text of DOI:10.1039/c9nj02503k

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Yellowish and blue luminescent graphene oxide quantum dots
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Bromination of tetrapyrrolic scaffolds: a sustainable approach
Giuseppe Pomaricoa,b, Federica Sabuzia, Valeria Contea and Pierluca Gallonia*
Received 00th January 20xx,
Accepted 00th January 20xx
A sustainable procedure developed for the bromination of organic substrates, such as olefins and small aromatic rings, has
been applied to porphyrin derivatives. The synthetic method, based on a V(V) or Mo(VI) catalyzed reaction, occurs in a two-
phase medium and uses cheap and environmental friendly reagents such as KBr and H2O2 as bromine source and primary
oxidant respectively. Compared to the classical protocols for porphyrinoids bromination, this approach is based on milder
and safer reaction conditions. The selective formation of mono or polybrominated substrates has been achieved by an
accurate tuning of key parameters (H2O2 and KBr amount, catalyst). While with Vanadium good results to obtain partially
substituted porphyrins have been gained, the fully peripheral functionalization can be obtianed with either Vanadium or
Molybdenum catalysis depending on the metal ion coordinated into the inner core.
DOI: 10.1039/x0xx00000x
substrate more robust toward the oxidative degradation. In
addition, the severe distortion from planarity induced by the
bulky substituents contribute to their efficiency as catalysts.
Recently the catalytic properties of simple and brominated
Introduction
Porphyrins represent the most important example in the family
of polypyrrolic macrocycles. The richness of properties of this
class of molecules, triggered the interest of scientists to exploit
them in different fields of research, ranging from medicine1 to
catalysis2 to chemical sensors3 or as dyes in DSSC.4 The strict
structure-property relationship explains the versatility of these
tetrapyrroles and their wide diffusion. The introduction of
substituents onto the peripheral positions as well as the
coordination of metal ions in the inner core makes possible to
obtain molecules whose features are tailored for the desired
applications. A very interesting modification of porphyrin
framework is the bromination reaction. On one hand,
brominated derivatives represent the starting point for further
modification of molecular framework achieved by cross
coupling methodologies, such as Suzuki, Heck, Stille or
Sonogashira reactions.5 This strategy allows the preparation, by
a bottom-up approach, of more sophisticated architecture that
otherwise would be barely accessible. On the other hand, the
properties of brominated macrocycle are affected by the
presence of bromine moieties. The electron-withdrawing atoms
shift both the oxidation and the reduction potentials to more
positive values, a modification that leads to a more difficult
electron abstraction and an easier electron addition.6 This
modification is advantageous when porphyrin derivatives are
exploited in catalysis. The variation of the cathodic and anodic
potentials increases the catalytic efficiency, making the
porphyrin oxidovanadium (IV) complexes have been
compared;7 the electron poor nature as well as the macrocycle
distortion allowed to obtain better results by using the bromine
containing macrocycle. The request for porphyrinoids scaffold
with different number of Br substituents encouraged the
pursuit for appropriate procedures to control number and
position of halogens. The most common procedures use NBS (N-
bromosuccinimide) or the corrosive and toxic Br2 as Br source,
and CHCl3, CCl4, o-dichlorobenzene or CH3OH as solvents.8-22
Although these methods allowed the preparation of the desired
products in good yields, nowadays sustainable and safer
procedures are greatly recommended, replacing the classical
synthetic methodologies with those as close to “green
chemistry” principles as possible.23 Among the different
sustainable procedures developed for the bromination of
organic substrates,24 we applied to tetrapyrrolic macrocycle our
bromination protocol, inspired by the mode of action of
Vanadium dependent bromoperoxidase enzymes (V-BrPO)25-29
whose working mechanism is depicted in Fig. 1.
In aqueous acid medium (pH = 1), V(V) or Mo(VI)30 based
catalysts, using H2O2 as primary oxidant, convert bromide into a
electrophile bromine equivalent intermediate (Br+, Br2 or BrO-),
that is transferred into the organic phase, where it reacts with
the substrate leading to the brominated products.
The main advantage of this method is the low cost and the
harmless nature of the catalyst, the oxidant and the bromine
source, that are dissolved in water. Moreover, as previously
reported in the functionalization of simple organic molecule,
a. University of Rome Tor Vergata, Department of Chemical Science and
Technologies, Via della Ricerca Scientifica, snc, 00133 Rome, Italy
b. University of Brescia, Department of Molecular and Translational Medicine, Viale
Europa, 11 – 25123 Brescia, Italy
25,28,30,31
the desired products can be obtained in good to
excellent yield.
† galloni@scienze.uniroma2.it; Tel: +39 0672504380.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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Scheme 1 Structure of the bromo-porphyrins derivatives obtained.
Regrettably the attempts to prepare monobrominated H2TPP
(2H-1) did not give fair results; indeed, with a slight excess of
KBr only a small amount of substrate reacted, while increasing
the amount of salt up to two equivalents, two new products
were detected on TLC, together with some residual TPP.
The UV-vis spectra of these compounds are consistent with the
formation of two isomeric forms of the dibrominated porphyrin,
where the second Br unit may lye on adjacent position to the
first Br or onto the opposite pyrrole ring. The formation of such
a complex mixture (TPP, BrTPP and antipodal dibrominated
derivative obtained in a similar 20% yield, while the adjacent
dibrominated compound was achieved in a lower 10 % yield) is
Fig. 1 Vanadium based two-phase system for bromination reactions
The scope of this work is to verify the possibility to prepare
halogenated porphyrinoids by the transition metals catalysed
system. For this reason, we investigated the insertion of a
variable number of Br units on the -pyrrolic positions of
tetraphenylporphyrin free base and its Cu, Ni and Zn complexes
(Scheme 1); in detail we were interested to mono, tetra and
octa-halogenated derivatives. Br8- and Br4-porphyrins are
interesting for the possible exploitation as catalyst, taking into
account the diffusion of porphyrins as catalytic material,32,33
while monohalogenated product allows to prepare substrates
for the application in the field of energy conversion.32,34 Good
results have been achieved, thus demonstrating that the
preparation of -brominated porphyrin derivatives can be
achieved by a modern and sustainable method.
a
common problem when the target molecule is the
monohalogenated macrocycle.
As reported in the literature (see for example tables in
references 19 and 22) insertion of only one Br unit can be
partially driven controlling the amount or the mode of addition
of brominating reagent. We then turned our attention to Zn-
complex that was reacted with 1.4 equivalent of KBr and 1
equivalent of H2O2. After 24 hours, final mixture showed the
presence of substrate as major product (isolated 29%) and a low
amount of a fraction (isolated: 21%) identified as the
monobrominated ZnTPP (Zn-4) by the deshielded singlet at 9.07
ppm for the hydrogen atom close the halogen moiety, while the
residual -pyrrolic positions integrate for 7 H. Reaction was
repeated several times increasing the amount of KBr up to 1.85
eq. Even if these attempts gave slightly better results in terms
of substrate conversion, at the same time the formation of a
second fraction was observed on TLC, reasonably ascribable to
some dibrominated product. To limit the competition between
ZnTPP and ZnBrTPP for reacting with the residual “Br+” species,
the organic phase/water ratio was raised up from of 3:1 to 12:1,
using 1 mL of aqueous solution; KBr amount was increased to
two equivalents to compel the substrate consumption. As a
matter of fact, a larger conversion was achieved but the
formation of some dibrominated derivative could not be
avoided. Considering the higher reactivity of Mo complex, this
metal was used in the presence of only 1.4 bromide equivalents,
obtaining similar results with respect to those reported with
Vanadium as catalyst. The formation of ZnBrTPP (Zn-4) was
estimated to be about 33% (residual TPP: 20%; dibrominated
species: 15%).
Results and discussion
Monobromination of porphyrin free-base and Zn complex:
tetraphenylporphyrin free base (H2TPP) was chosen as model
substrate for the transition metals catalysed halogenation
experiments, and the following conditions were generally
adopted: 0.02 mmol of substrate dissolved in 3-4.5 mL of
CH2Cl2, 1 or up to 2.5 mL (volume was increased when more
then 10 equivalents of salts were used) of aqueous solution at
pH = 1 with 0.5 equivalent of catalyst (Vanadium or
Molybdenum salts). The amount of KBr and H2O2 was tuned
depending by the target brominated molecules.
To note, V(V) catalyst was the initial choice, while the more
reactive Mo(VI) was adopted when results with Vanadium were
unsatisfactory. The monobrominated porphyrin was our first
target molecule; to achieve the preparation of this compound
we initially used a 1.25/1/1 KBr/H2O2/H2TPP ratio; however,
since the metal catalyst triggers the decomposition of hydrogen
peroxide, in some case a second portion of H2O2 (usually half
equivalents with respect the first one) was added after 6 hours.
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Polybromination of porphyrin free-base: due to the tendency
of porphyrin to easily form multifunctionalized derivatves, we
decided to investigate the preparation of polybrominated
macrocycles. This kind of molecules attracted attention in the
last decade because they can be further modified (by cross
coupling methodologies) and anchored to metal oxide surfaces
allowing the exploitation as dye in the DSSC.34
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It is well known that the maximum level of bromination
achievable for porphyrin free base is the tetrafunctionalization,
and that only one regioisomer is obtained, where the halogen
atoms are located on the antipodalic position (the “iminic”
pyrrole).16 The remarkable selectivity of this process prompted
us to apply the Vanadium catalysed method for the preparation
of H2Br4TPP. The reaction was initially performed on 0.02 mmol
of tetraphenylporphyrin dissolved in 3 mL of CH2Cl2, 1 mL of
aqueous phase at pH = 1 and containing 0.01 mmol of V-based
catalyst; finally, 10 times excess of KBr and overall 12
equivalents of oxidant (two partitioned addition, 8 and 4
equivalents), were used to achieve the desired product. The
analysis of the final mixture revealed the presence of one main
product, which was identified as the 2,3,12,13-Br4-
Tetraphenylporphyrin (H2Br4TPP) (2H-3) by UV-vis18,20 (Soret
band at 436 nm and three weaker absorbance in the 500-700
Fig. 2 UV-vis spectra of H2TPP, tri- and tetrabrominated derivatives.
This result is noteworthy because demonstrates the
effectiveness of such sustainable process applied to the
tetrapyrrolic macrocycle, leading to a more than satisfying yield
for the H2Br4TPP formation. In fact, such value is quite close to
what obtained with classical method.18
1
region, see Fig. 2), and H NMR spectroscopy, where a singlet
integrating for 4 H resonates at 8.69 ppm. H2Br4TPP was isolated
in a 34% yield.
Fully bromination of porphyrin Zn and Cu-complexes: while
bromination of free base permits the insertion of one to four
bromine moieties, to achieve the fully substitution of peripheral
positions it is necessary to use a metal-complex as substrate.
The higher stability due to the metal coordination, limits the
decomposition of the substrate (octabromination usually
requires stronger reaction conditions); moreover, the increased
symmetry of metal complexes promotes the functionalization
of all the -pyrrolic positions. Indeed, the information about the
“fixed double bond” entity that is transmitted via the NH
tautomerism, is lost because of the metal ion insertion; thus,
the remaining -pyrrolic positions have almost the same
reactivity.16 For these reasons, the octabromination of easily
accessible Zn2+, Cu2+ and Ni2+ TPP complexes was investigated.
Zn2+ and Ni2+ ions were chosen because the diamagnetic nature
of the complexes permits the identification of the products by
NMR spectroscopy. In the case of Cu-porphyrin, despite its
paramagnetism hampers NMR analysis of the bromination
products, we decided to investigate it because of its large
stability which should limit the decomposition under the
reaction conditions. Then, the metal ion can be removed, thus
permitting the characterization of the product also by NMR
spectroscopy and the preparation of a wide range of different
complexes.
A smaller amount (15%) of a compound with a lesser grade of
bromination, as judged by the lower red shift of Soret band, (vs.
H2TPP) was isolated. This fraction was identified as the 2,3,12-
Br3-Tetraphenylporphyrin (H2Br3TPP) (2H-2) by comparison of
its UV-vis spectrum with that reported in literature.20 The
nature of this derivative was also confirmed by 1H NMR analysis,
where several signals either for the pyrrolic region (8.69-8.86
ppm) and for the inner NH were detected, as expected due to
the product low symmetry.
The presence of H2Br3TPP as by-product of the H2Br4TPP
preparation, suggests that the former could be selectively
obtained by decreasing the substrate/reactants ratio, while
rising up the reagents/substrate ratio the process selectivity
should be shifted toward the formation of H2Br4TPP. As
assumed, when the reaction was performed with 7.5
equivalents of KBr, H2Br3TPP was obtained in a 48% yield, while
only a small amount (5%) of H2Br4TPP was collected.
As previously discussed, to foster the substrate toward the
insertion of four Br moieties, a larger excess of salt (10 eq.) and
oxidant (20 eq. in one portion) was used, while no variations
were made to the others reaction conditions. The yield for
H2Br4TPP was raised up to 47%, while H2Br3TPP was detected in
very small amount (less then 10%).
These experimental conditions were chosen: substrate (usually
0.02 mmol) dissolved in 4.5 mL of CH2Cl2 (volume of the organic
solvent was improved to guarantee the solubilisation of the
complexes), 2 or more mL of aqueous phase at pH = 1 with at
least 0.5 eq. of catalyst (Exact values are given in the
experimental section).
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To ascertain the feasibility of the reaction on porphyrin H2O2. Pondering over the results reported for thisVcieowmArptilcelexOanlninde
complexes, the bromination was initially performed on ZnTPP the different reactivity of Cu-porphyrin (which is more electron
DOI: 10.1039/C9NJ02503K
by using the same reaction conditions leading to the H2Br4TPP, poor than Zn-complex, so less reactive toward electrophiles) we
i.e. 10 times excess of KBr and overall 12 equivalents of oxidant. increased the reactants amount to 24 and 32 equivalents
A main greenish-violet fraction was collected; the red-shift of respectively. The stability of this complex permitted to double
the Soret band observed at the UV-vis spectrum was consistent the catalyst amount, while with ZnTPP as the substrate 1 eq. of
with the formation of polybrominated product. Nonetheless, Vanadium led to a marked decomposition. It should be
several signals were detected in the 8.5-9.0 ppm region of the considered that these values correspond to 3 eq. of Br-, 4 eq. of
1H NMR spectrum, suggesting the presence of a mixture of oxidant and 12.5 % by mol of Vanadium versus any -pyrrolic
differently halogenated derivatives. Even if this result is not position.
useful from a synthetic point of view, it confirmed that the After the reaction work up, the mixture was analysed by UV-vis
bromination could be performed also with Zn-complex as spectroscopy that showed a spectroscopical pattern similar to
starting material. Assuming the formation of a mixture of what reported in literature for CuBr8TPP with a strong red
regioisomers of ZnBr4TPP (we adopted the procedure for shifted and splitted Soret band.13 Also TLC was promising: a
H2Br4TPP preparation), the conversion was ca. 60%. The small amount of decomposed material was detected, clearly
reaction was then attempted with 16 equivalents of KBr and much less with respect to what reported in the case of the Zn-
12+6 eq. of H2O2 and a green fraction was collected. The complex, while the absence of the substrate indicates a
increased bromination degree was highlighted by the larger complete conversion into the brominated derivatives (Cu-6).
red-shift of Soret band located at 447 nm (usually, the higher is Mixture was roughly purified to remove the decomposition
the number of Br atoms, the larger is the bathochromic products, while the fractions containing the brominated species
effect35), even if this data still indicates the uncompleted (Br8 as main product contaminated by the Br7 porphyrin) were
functionalization of the macrocycle. This supposition was collected all together. Because of the paramagnetic nature of
corroborated by the NMR spectrum, where the presence of the Cu-porphyrins hampers the NMR characterization of the
several scattered singlets for -pyrrolic positions still indicates compounds, we performed the isolation and the
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the presence of partially substituted macrocycles.
characterization of the Br8-porphyrin after its conversion into
A further increase of reactants (KBr: 20 eq.; H2O2 16+8 eq.), the diamagnetic Zn-complex. First of all, the mixture was
allowed achieving a slightly improvement in the substrate demetalated treating a CHCl3 solution of the porphyrin with
transformation as showed by the spectroscopical analysis: Soret concentrate H2SO4.37 The course of the reaction was monitored
band was located at 466 nm while just traces of not-brominated by UV-vis spectroscopy where the metal ion removal was
1
positions were observed in the H NMR spectrum (residual - highlighted by the appearance of the characteristic band of the
pyrrolic protons). The fully brominated Zn-complex (Zn-5) was porphyrin dication at 735 nm (Figure 3); once completed, the
obtained in 22% yield. To the best of our knowledge it mixture was neutralized and the reaction for the Zn insertion
represents the first example of direct fully bromination of Zn- carried out.
tetraphenylporphyrin, usually obtained by removal of Cu ion Substituted porphyrins are strongly non-planar and the
from CuBr8TPP followed by remetalation with Zn salt.13 Some distortion of the macrocycle facilitates the protonation of the
example of bromination of Zn-tetraarylporphyrin have been inner core which may occurs also during the chromatographic
carried out, mainly on macrocycle bearing 2,6-disubstituted purification. To avoid this problem the central nitrogens were
meso phenyl rings.9,10,14,15 Here, the steric hindrance of the protected by coordination of the diamagnetic Zn2+. The
substituents may prevent the Zn ion displacement, while the following purification by alumina column yielded two fractions,
bromination of ZnTPP produces an unexpected two sided ring the first having a residual hydrogen on pyrrolic positions as
opening of the substrate.36
highlighted by 1H NMR (singlet at 8.51 ppm), while for the
Albeit encouraging, the results were not really satisfactory. second one only the signals for the phenyl rings were observed.
Many attempts to induce the complete bromination were The ZnBr8TPP (Zn-5) was finally isolated in a 45% yield.
carried out, changing the KBr and H2O2 amount, the oxidant Noteworthy, this is the yield calculated after three synthetic
mode of addition, volume of acidic solution or catalyst, but the steps (bromination-demetalation-remetalation with Zn). Taking
increase of octabrominated product generally occurs together into account the values reported in literature for the
with a large decomposition. Moreover, a partial demetalation demetalation of CuBr8TPP to H2Br8TPP with H2SO4, (68%)37 and
because of the low pH was seen. For this reason, the more the Zn insertion into the H2Br8TPP (90%),13 we computed a 73%
robust CuTPP was used as substrate; the disadvantage of the yield for the fully halogenation of the copper complex (Cu-6), an
paramagnetic nature of this complex can be easily bypassed by almost equal value to that achieved with molecular Br2 (73 vs
acidic Cu removal. Since CuTPP is the substrate chosen for the 75%).
fully bromination performed with one of the most famous (but The above mentioned conditions allow to obtain the best
not sustainable) classical method,13 the achievement of outcome; when the same amount of hydrogen peroxide was
CuBr8TPP by the sustainable approach would allow to easily added in two portions or when more equivalents of reagents
compare these synthetic strategies.
were employed, ZnBr8TPP was obtained in the 25-35% range.
The best conditions for the bromination of Zn-complex were the
following: 20 equivalents of KBr and overall 24 of equivalents
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method, with advantage of avoiding the exploitation of toxic
reagents.
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Finally, to consider the sustainability of the process the results
obtained with this approach were compared with those of the
classical procedures using the corresponding E factor (kg of by-
product per kg of product), a parameter that better describes a
sustainable processes since it does not consider only the
“classical yield”.39,40 The values obtained, indeed, do not
generally underline a substantial decrease of E (with the
noticeable exception of CuBr8TPP), nonetheless an
“environment friendly process” not only minimizes the
formation of undesired products but also optimizes the
utilization of resources, decreases the energy consumption and
overall uses substances as less hazardous as possible thus
following some of the “Green Chemistry” principles.23 By the
pure E-factor values (see table S1 in the Supplementary), it
seems that the methods described in this paper is not
advantageous with respect to the common systems to
brominate tetrapyrrolic macrocycle; nevertheless, the
transition metals catalyzed bromination is far better
considering hazardousness of the reagents employed and the
lower energetic cost.
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Fig. 3 UV-vis spectra of CuBr8TPP (green line) and [H4Br8TPP]2+ indicating the ongoing at
demetalation.
Fully bromination of porphyrin Ni-complex: after the
Table 1. Yields for the sustainable bromination of porphyrin derivatives.
achievement of
a synthetic protocol for the complete
Yield
literature
(ref.)
halogenation of Zn and Cu-porphyrins, the reactivity of Ni-
complex was investigated. As a first step, we compared the
behaviour of Zn, Cu and Ni porphyrins, running on the latter
bromination with the same reactants ratios previously used for
the preparation of ZnBr8TPP and CuBr8TPP. Both methods
partially failed. Even if no more starting material was detected
at the end of the reaction, suggesting the complete substrate
conversion, the Soret band of the product was less red-shifted
with respect to published spectroscopical data.13,17 The amount
of KBr and H2O2 was increased up to 32 eq, with 0.5 eq. of
Vanadium-based catalyst. Once more, the NMR spectrum
showed several -pyrrolic signals. The reactivity of the system
was increased heating the system at 45 °C (dichloromethane
was replaced with 1,2-dichloroethane); regrettably the
functionalization of all the peripheral positions was not
achieved (final products have the same Rf, thus the purification
by chromatographic methods was unmanageable) and a
partially demetalation of the complexes has been observed.
A limit of the Vanadium catalyzed reaction is the fast peroxide
decomposition operated by the metal.26 To overcome this
drawback, V was replaced with the more reactive Mo
catalyst;30,38 when the reaction was performed at 20 °C, a more
complete grade of substitution was achieved. Again, the 1H
NMR spectrum showed the presence of traces of macrocycle
with residual protons contaminating the more abundant
NiBr8TPP (Ni-7). When the reaction was carried out at higher
Catalyst,
eqs.
Yield
this work
Product
KBr eq.
H2O2 eq.
H2Br3TPP
H2Br4TPP
ZnBrTPP
ZnBr8TPP
CuBr8TPP
NiBr8TPP
7.5
10
1.4
20
24
32
6+3a
20
V, 0.5
V, 0.5
48%
47%
33%
22%b
73%
25%
40% (19)
65% (17)
51%b (20)
54%c (12)
75% (12)
85% (16)
1+1a
16+8a
32
Mo, 0.5
V, 0.5
V, 1.0
32
Mo, 0.5
[a] Second portion of H2O2 added after 6 hours; [b] 3,5-di-tert-butylphenyl groups
on meso positions [c] Multi-steps procedure
DFT calculations: As already mentioned above, the increasing
bromination level of the macrocycle implies a bathochromic
shift in the UV-vis spectra. Such effect is due to different
reasons: the electron-withdrawing effect of the bromine
substituents, as well as to the lost of planarity of the macrocycle
once brominated for steric hinderance
Hence, DFT calculations have been carried out in the vacuum,
to confirm such saddling effect. Geometry optimization of the
polybrominated metal and metal-free TPPs has been performed
using B3LYP hybrid functional and 6-31G(d) basis set. According
to UV-vis data, the planar TPP results significantly tilted when
four or eight Br atoms are introduced onto peripheral positions.
A more severe distortion is observed in highly substituted
derivatives (Fig. 4).
temperature,
a
larger decomposition was detected
(Conversion: 25% at 20 °C and 8% at 45 °C).
The best results obtained for the preparation of bromo-
derivatives are resumed in table 1. The reported values indicate
that the transition metal-catalysed system gave comparable
yields (H2Br3TPP, CuBr8TPP) to those reported with literature
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Fig. 5 Calculated dihedral values and M-N.
Conclusions
Vanadium or Molybdenum catalyzed bromination represents
an innovative and sustainable strategy for the functionalization
of tetrapyrrolic macrocycles. Some noteworthy results have
been achieved: substitution of NBS or the toxic and corrosive
Br2 with the much safer KBr as bromine source; use of a cheap
oxidant as H2O2, also characterized by the highest active oxygen
content after O2 itself; and last but not the least the use of
CH2Cl2 in place of the more dangerous CHCl3 or CCl4 as organic
solvents. This kind of process has been made possible by the
ability of the transition metal to convert a safe but unreactive
form of Br (Br-) in a reactive, electrophile species by using a
common oxidant such as H2O2.
By the amount of catalyst used, the method seems to be quite
far from a catalytic process. Anyway, two important points
should be considered: first of all, up to eight peripheral
positions may undergo the functionalization, lowering the real
catalyst/substrate ratio (12.5% by mol. for the fully brominated
species). Then, the active catalytic system requires low pH and
H2O2. Since the decomposition of hydrogen peroxide is
triggered also by the low pH, a large amount of transition metals
is needed to allow the reaction to quickly take place before the
unavoidable reactant decomposition. Finally, to force the
reaction toward the formation of the desired product, the
amount of KBr and H2O2 has been modified to overcome the low
reactivity of porphyrin -positions. Of course, too large
reactants excess is inadvisable because it would make the
process not sustainable. Obviously, a higher yield is a desirable
outcome to avoid or simplify the purification step, enhancing
the sustainability of the process. In some cases our procedure
allowed to achieve the target molecules with a comparable
(H2Br3TPP) or superior (CuBr8TPP) yields with respect to those
obtained by the literature methods, demonstrating that the
“sustainable way” for the halogenation of tetrapyrrole
Fig. 4 DFT optimized geometry for H2TPP and brominated porphyrins, side view. Bromine
atom is represented in red; nitrogen in blue; carbon atoms are in grey and hydrogen in
white.
Dihedral values have been calculated for all compounds (Fig.
5).41,42 Here, the saddling of the macrocycle is highlighted by the
significant widening of dihedrals. Moreover, M-N distances
have been calculated and results show that the bromine
substitution at the peripheral position slightly affect also the
metal coordination. As a matter of fact, fully substituted
porphyrins show a M-N distance of 2.03 Å for ZnBr8TPP and 1.91
Å for NiBr8TPP. Conversely, the tetrasubstituted derivatives
present the same values for the M-N1 bond, while shorter
values have been calculated for M-N2, where N2 represents the
nitrogen belonging to the non-brominated pyrroles.
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macrocycles periphery is a practical and effective approach. H2TPP (12.2 mg, 0.02 mmol) was dissolved in 3 mL of CH2Cl2,
View Article Online
Moreover, by an accurate optimization of the reaction then 1 mL of aqueous solution at pH =D1OI:(H10C.1l0O349)/Cc9oNnJt0a2in50in3Kg
conditions, considerable improvements of the yields may be NH4VO3 (1.1 mg, 0.01 mmol) and KBr (17.8 mg, 0.15 mmol) was
anticipated, in order to reach satisfactory results for a wide added, followed by H2O2 (46 L 2.6 M, 0.12 mmol). Mixture was
series of porphyrin derivatives, as already described for simple vigorously stirred at 20 °C for 6 hours; a second aliquot of H2O2
arenes or alkenes.25,28,30-31. A plausible explanation for the (23 L 2.6 M, 0.06 mmol) was added and mixture stirred for
difficulties observed in the case of ZnBr8TPP and NiBr8TPP further 18 hours, then organic phase was washed with satured
formation, is the partial demetalation/protonation of the inner NaHCO3, water and finally dried over Na2SO4. Residue was
core which deactivate the peripheral positions (Zn-complex purified by silica gel column eluted with CH2Cl2/petroleum ether
easily undergoes Zn removal under acidic condition) or of a 2:1; fractions containing the H2Br3TPP were collected, solvent
marked decomposition due to the presence of oxidant, catalytic removed under vacuum and residue crystallized from
metals and long reaction time. However, the formation of CH2Cl2/MeOH. Yield: 8.2 mg, 48%.
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H2Br3TPP, H2Br4TPP and CuBr8TPP in more than acceptable UV-vis (CH2Cl2) max (nm) [log , M-1, cm-1]: 428 (5.42), 525
amount, suggests that only some substrates may suffer of such (4.25), 562 (sh), 602 (3.54), 663 (3.73).
a drawback. Much more, it should be highlighted the versatility 1H NMR (400 MHz, CDCl3):  = 8.86-8.77 (m, 3H, -pyrrole), 8.73-
of the procedure, which allows the insertion of a variable 8.69 (m, 2H, -pyrrole), 8.19-8.03 (m, 8H, meso o-phenyl), 7.81-
number of Br moieties on tetrapyrrolic macrocycles, free base 7.71 (m, 12H, meso m-phenyl + meso p-phenyl), -2.87 (s, 1H,
or metal complexes.
inner NH), -2.99 (s, 1H, inner NH).
Finally, a further “environment friendly” aspect is connected Elemental Analysis: calcd. for C44H27Br3N4 C, 62.07; H, 3.20; N,
with the lower energy consumption, since the reaction 6.58: found C, 61.82; H, 3.09; N, 6.62
proceeds at room temperature, at odd with many literature Synthesis
of
2,3,12,13-Tetrabromo-5,10,15,20-
protocols. tetraphenylporphyrin (H2Br4TPP) (2H-3).
In conclusion, these preliminary results clearly demonstrate H2TPP (12.2 mg, 0.02 mmol) was dissolved in 3 mL of CH2Cl2,
that there is an open new way to obtain differently brominated then 1 mL of aqueous solution at pH = 1 (HClO4) containing
porphyrinoids with modern and sustainable protocol, indeed NH4VO3 (1.1 mg, 0.01 mmol) and KBr (23.8 mg, 0.20 mmol) was
further studies to optimize the reactions are warranted.
added, followed by H2O2 (38 L 10.4 M, 0.40 mmol). Mixture
was vigorously stirred at 20 °C for 24 hours, then organic phase
was washed with satured NaHCO3, water and finally dried over
Na2SO4. Residue was purified by silica gel column eluted with
CH2Cl2/petroleum ether 2:1; a small amount of H2Br3TPP eluted
first, followed, by a red-brownish band fractions containing the
H2Br4TPP; solvent was removed under vacuum and residue
crystallized from CH2Cl2/MeOH. Yield: 8.7 mg, 47%.
Experimental
Instrumentation: UV-vis spectra were recorded in CH2Cl2 with a
Shimadzu UV/Vis spectrophotometer UV-2401 PC. 1H NMR
spectra were recorded at 300 K with a Bruker Avance III 400
BBFO spectrometer operating at 400 MHz. Chemical shifts are
given in ppm to residual solvent (CHCl3 = 7.26 ppm).
Purity of compounds was checked by HPLC with a Shimadzu
LC10AT Liquid Chromatography equipped with a SPD10AV UV-
vis detector and a Chiralcel OD column (250x4.6 mm,10 m
particles size, Daicel Chemical Industries) with toluene as
eluent; detector was set at abs = 550 nm. It was measured a
purity > 99% for H2Br3TPP, H2Br4TPP, ZnBrTPP and > 98% for
ZnBr8TPP and NiBr8TPP.
UV-vis (CH2Cl2) max (nm) [log , M-1, cm-1]: 436 (5.50), 534
(4.31), 612 (3.56), 682 (4.03).
1H NMR (400 MHz, CDCl3):  = 8.69 (s, 4H, -pyrrole), 8.17-8.16
(m, 8H, meso o-phenyl), 7.81-7.74 (m, 12H, meso m-phenyl +
meso p-phenyl), -2.81 (s, 2H, inner NH).
Elemental Analysis: calcd. for C44H26Br4N4 C, 56.81; H, 2.82; N,
6.02: found C, 56.34; H, 2.91; N, 6.22
Synthesis of [2,3,7,8,12,13,17,18-Octabromo-5,10,15,20-
tetraphenylporphyrinato]Zinc (ZnBr8TPP) (Zn-5).
Materials: Silica gel 60 (70–230 mesh, Sigma–Aldrich) was used
for column chromatography. Reagents and solvents (Aldrich,
Fluka, Carlo Erba) were of the highest grade available and were
used without further purification.
ZnTPP (13.5 mg, 0.02 mmol) was dissolved in 4.5 mL of CH2Cl2,
then 2.5 mL of aqueous solution at pH = 1 (HClO4) containing
NH4VO3 (1.1 mg, 0.01 mmol) and KBr (47.6 mg, 0.40 mmol) was
added, followed by H2O2 (31 L 10.4 M, 0.32 mmol). Mixture
was vigorously stirred at 20 °C for 6 hours; a second aliquot of
H2O2 (16 L 10.4 M, 0.16 mmol) was added and mixture stirred
for further 18 hours, then organic phase was washed with
satured NaHCO3, water and finally dried over Na2SO4. (Note:
some demetalation may occur, as evidenced by a large band
around 710 nm; the metal complex can be restored heating the
reaction mixture with a satured solution of Zn(AcO)2 in
methanol for a few minutes). Residue was purified by silica gel
column eluted with CH2Cl2/petroleum ether 1:1, followed by
PLC (silica gel, CH2Cl2/petroleum ether 1:1). Fractions
containing the ZnBr8TPP were collected, solvent removed under
5,10,15,20-Tetraphenylporphyrin
Tetraphenylporphyrinato]Ni(II)
(H2TPP),43
(NiTPP)44,
[5,10,15,20-
[5,10,15,20-
Tetraphenylporphyrinato]Cu (II) (CuTPP)44, and [5,10,15,20-
Tetraphenylporphyrinato]Zn(II) (ZnTPP)44 were prepared
according to literature methods.
DFT Calculation: DFT geometry optimizations have been
performed with Gaussian 16 rev. A.0345, using the B3LYP
functional and a 6-31G (d) basis set.
Synthesis of 2,3,12-Tribromo-5,10,15,20-tetraphenylporphyrin
(H2Br3TPP) (2H-2).
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reduced pressure and residue crystallized from CH2Cl2/MeOH. was added, followed by H2O2 (61 L 10.4 M, V0ie.w64ArticmlemOnoliln)e.
DOI: 10.1039/C9NJ02503K
Yield: 5.7 mg, 22%.
Mixture was vigorously stirred at 20°C for 6 hours; a second
UV-vis (CH2Cl2) max (nm) [log ε, M-1, cm-1]: 349 (4.65) 466 (5.39), aliquot of H2O2 (61 L 10.4 M, 0.64 mmol) was added and
589 (4.12), 656 (4.08). mixture stirred for further 18 hours, then organic phase was
1H NMR (400 MHz, CDCl3):  = 8.13 (d, 8H, J = 6.93 Hz, meso o- washed with satured NaHCO3, water and finally dried over
phenyl), 7.82-7.72 (m, 12H, meso m-phenyl + meso p-phenyl) Na2SO4. Residue was purified by silica gel column eluted with
Elemental Analysis: calcd. for C44H20Br8N4Zn C, 40.36; H, 1.54; N, CH2Cl2/petroleum ether 1:1; fractions containing the NiBr8TPP
4.28; found C, 40.41, H, 1.42; N, 4.31 were collected, solvent removed under reduced pressure and
Synthesis of [2,3,7,8,12,13,17,18-Octabromo-5,10,15,20- residue crystallized from CH2Cl2/MeOH. Yield: 6.5 mg, 25%.
tetraphenylporphyrinato]Copper (CuBr8TPP) (Cu-6).
UV-vis (CH2Cl2) max (nm) [log , M-1, cm-1]: 342 (4.43), 449
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CuTPP (27 mg, 0.04 mmol) was dissolved in 9 mL of CH2Cl2, then (5.45), 560 (4.16), 596 (sh).
5 mL of aqueous solution at pH = 1 (HClO4) containing NH4VO3 1H NMR (400 MHz, CDCl3):  = 7.92-7.90 (m, 8H, meso o-phenyl),
(4.7 mg, 0.04 mmol) and KBr (114 mg, 0.96 mmol) was added, 7.75-7.65 (m, 12H, meso m-phenyl + meso p-phenyl).
followed by H2O2 (123 L 10.4 M, 1.28 mmol). Mixture was Elemental Analysis: calcd. for C44H20Br8N4Ni C, 40.57; H, 1.55; N,
vigorously stirred at 20 °C for 24 hours, then organic phase was 4.30; found C, 41.02; H, 1.62; N, 4.19
washed with satured NaHCO3, water and finally dried over Synthesis
of
[2-Bromo-5,10,15,20-
Na2SO4. Residue was purified by neutral Al2O3 (Grade III) eluted tetraphenylporphyrinato]Zinc (ZnBrTPP) (Zn-4).
with CHCl3. Fractions containing the CuBr8TPP were collected, ZnTPP (13.5 mg, 0.02 mmol) was dissolved in 12 mL of CH2Cl2,
solvent removed under reduced pressure and residue then 1 mL of aqueous solution at pH = 1 (HClO4) containing
crystallized from CH2Cl2/MeOH. Since mixture containing (NH4)2MoO4 (1.8 mg, 0.01 mmol) and KBr (3.3 mg, 0.028 mmol)
CuBr8TPP was contamined by some CuBr7TPP yield was not was added, followed by H2O2 (20 L 1.0 M, 0.02 mmol). Mixture
calculated and product was identified by comparison of the UV- was vigorously stirred at 20°C for 6 hours; a second aliquot of
vis spectra with literature data.12 Product was directly used for H2O2 (20 L 1.0 M, 0.02 mmol) was added and mixture stirred
the demetalation and the Zn insertion steps.
Synthesis of 2,3,7,8,12,13,17,18-Octabromo-5,10,15,20- satured NaHCO3, water and finally dried over Na2SO4. Residue
tetraphenylporphyrine H2Br8TPP and of [2,3,7,8,12,13,17,18- was purified by PLC (silica gel column eluted with
for further 18 hours, then organic phase was washed with
Octabromo-5,10,15,20-tetraphenylporphyrinato]Zinc
(ZnBr8TPP) (Zn-5).
CH2Cl2/petroleum ether 3:4; fractions containing the ZnBrTPP
were collected, solvent removed under reduced pressure and
Mixture containing the CuBr8TPP (47 mg) was dissolved in 20 mL residue crystallized from CH2Cl2/MeOH. Yield: 4.9 mg, 33%.
of CHCl3, then 0.8 mL of concentrated sulphuric acid was added UV-vis (CH2Cl2) max (nm) [log ε, M-1, cm-1]: 420 (5.56), 549
and mixture vigorously stirred for 5 minutes. Demetalation (4.27), 584 (3.93).
process was monitored by UV-vis spectroscopy as indicated by 1H NMR (400 MHz, CDCl3):  = 9.07 (s, 1H, -pyrrole), 8.94 (d,
the dication porphyrin band at 735 nm. Reaction was then 1H, J = 4.75 Hz, -pyrrole), 8.91 (m, 3H, -pyrrole), 8.88 (d, 1H,
poured into 30 mL of water, organic phase extracted with CHCl3, J = 4.74 Hz, -pyrrole), 8.83 (d, 1H, J = 4.74 Hz, -pyrrole), 8.21-
neutralized with satured NaHCO3, washed with water, then 8.17 (m, 6H, meso o-phenyl), 8.07-8.05 (m, 2H, meso o-phenyl),
dried over Na2SO4. Residue was purified by basic Al2O3 (Grade 7.79-7.68 (m, 12H, meso m-phenyl + meso p-phenyl).
III) eluted with CHCl3. Fractions containing the porphyrins free Elemental Analysis: calcd. for C44H27BrN4Zn*H2O C, 68.19; H,
base were collected, solvent reduced to 20 mL and a satured 3.77; N, 7.23; found C, 68.52; H, 3.92; N, 7.15
solution of Zn(OAc)2·2H2O in methanol was added. Reaction
was heated to reflux for 10 minutes and complex formation
monitored by UV-vis spectroscopy. Solvent was removed and
Conflicts of interest
residue purified by neutral Al2O3 (Grade III) eluted with
CHCl3/hexane 3:2 to collected the first band identified as the
ZnBr7TPP by the residual singlet (8.56 ppm) observed at 1H NMR
spectroscopy, then CHCl3/hexane 4:1 to collect the desired
ZnBr8TPP, crystallized from CH2Cl2/MeOH. Yield: 23.5 mg, 45%
(Note: yield has been calculated after three steps, with respect
CuTPP as the starting material).
There are no conflicts to declare.
Acknowledgements
University of Rome Tor Vergata funds SUSCARE, “Mission Sus-
tainability” is acknowledged.
UV-vis (CH2Cl2) max (nm) [log ε, M-1, cm-1]: 349 (4.65) 466 (5.39),
589 (4.12), 656 (4.08).
Notes and references
1H NMR (400 MHz, CDCl3):  = 8.13 (d, 8H, J = 6.93 Hz, meso o-
phenyl), 7.82-7.72 (m, 12H, meso m-phenyl + meso p-phenyl)
Synthesis of [2,3,7,8,12,13,17,18-Octabromo-5,10,15,20-
tetraphenylporphyrinato]Nickel (NiBr8TPP) (Ni-7).
NiTPP (13.4 mg, 0.02 mmol) was dissolved in 4.5 mL of CH2Cl2,
then 2 mL of aqueous solution at pH = 1 (HClO4) containing
(NH4)2MoO4 (1.8 mg, 0.01 mmol) and KBr (76.1 mg, 0.64 mmol)
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