Facile synthesis of phthalocyanine at low temperature with diisopropylamide anion as nucleophile

Article abstract of DOI:10.1016/j.tetlet.2015.05.086

Abstract Phthalocyanine has been synthesized from phthalonitrile and lithium diisopropylamide (LDA) at ambient or even lower temperatures. In this novel, facile, and low reactant-consuming method, diisopropylamide anions work as nucleophile to initiate the low temperature reaction. The mechanism has been rationalized by density functional theory (DFT) calculation. Our method is also useful for the transformation of some phthalonitrile derivatives to phthalocyanine compounds.

Full text of DOI:10.1016/j.tetlet.2015.05.086

Accepted Manuscript
Facile synthesis of phthalocyanine at low temperature with diisopropylamide
anion as nucleophile
Wei Zheng, Cheng-Zhang Wan, Jing-Xuan Zhang, Cheng-Hui Li, Xiao-Zeng
You
PII:
S0040-4039(15)00919-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.05.086
TETL 46358
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
17 April 2015
20 May 2015
22 May 2015
Please cite this article as: Zheng, W., Wan, C-Z., Zhang, J-X., Li, C-H., You, X-Z., Facile synthesis of phthalocyanine
at low temperature with diisopropylamide anion as nucleophile, Tetrahedron Letters (2015), doi: http://dx.doi.org/
10.1016/j.tetlet.2015.05.086
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Tetrahedron Letters
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Facile synthesis of phthalocyanine at low temperature with diisopropylamide anion as
nucleophile
Wei Zheng, Cheng-Zhang Wan, Jing-Xuan Zhang, Cheng-Hui Li*, Xiao-Zeng You ∗
State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Advanced
Microstructures, Nanjing University, Nanjing 210093, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Phthalocyanine has been synthesized from phthalonitrle and lithium diisopropylamide (LDA) at
ambient or even lower temperature. In this novel, facile and low reactant-consuming method,
diisopropylamide anions work as nucleophile to initiate the low temperature reaction. The
mechanism has been rationalized by density functional theory (DFT) calculation. Our method is
also useful for the transformation of some phthalonitrile derivatives to phthalocyanine
compounds.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Phthalocyanine
Low temperature synthesis
Lithium diisopropylamide
1. Introduction
Phthalocyanine (Pc) and its derivatives have been found useful
2
in various fields, such as dyes and pigments,1, chemical
4
sensors,3,
catalysts,5-8 medical applications,9-11 and
photosensitizers for photodynamic therapy,12-14 etc. Thus far,
most of phthalocyanine and their derivatives were prepared by
condensation of phthalonitriles with lithium n-petanolate or DBU
in refluxing pentanol, or by fusion methods from phthalic
anhydrides or its derivatives.6-16 These reactions were performed
at a high temperature (100 ~ 300 °C) making them not only
energy- but also time-consuming. Moreover, reactions of
phthalonitrile with thermal sensitive substituents are always
unfavorable at high temperature.17 Therefore, it is important to
develop new methods through which phthalocyanine can be
obtained at ambient or even lower temperature.
Scheme 1.
Mechanism of phthalocyanine’s formation started from
phthalonitrile and alkoxy anion.
Previously, several reports have been devoted to the low
temperature synthesis of phthalocyanines.17-22 However, these
procedures require excess base (several to ten-fold excess),18
prolonged reaction time (hours, days or even weeks),17-19 or have
to be performed with the help of ultrasonic treatments, irradiation
or electrolysis.20-22 It is still a challenge to develop a low
temperature method to produce phthalocyanine in a facile and
reactant-saving way.
The mechanism for the formation of phthalocyanine ring from
phthalonitrile and alkoxy anion (RO-) was shown in Scheme 1,
where RO- functions as nucleophlile. The existence of sufficient
alkoxy anion is essential to activate the reaction. However,
pentanol could only be deprotonized adequately at high
temperature by organic base (DBU) or lithium atom. In contrast,
with organic metal salts such as MeONa, numerous organic ions
(MeO- for MeONa) could be obtained easily through ionization
process in organic solvents at room temperature. Therefore,
organic metal salts might be useful for the formation of
phthalocyanine at lower temperature in comparison with
pentanol/DBU.
———
∗ Corresponding author. Tel.: +86-25-83592969; fax: +86-25-83314502; e-mail: chli@nju.edu.edu
∗ Corresponding author. Tel.: +86-25-83592969; fax: +86-25-83314502; e-mail: youxz@nju.edu.edu

2
Lithium diisopropylamide (LDA) in tetrahydrofuran (THF) is
that higher temperature leads to more products, which is in
accordance with the previous reports.7 It is noteworthy that
moderate yield of phthalocyanine can still been successfully
obtained at -20 °C, which is unprecedented in previous work.
Notably, a very small amount of phthalocyanine was obtained at
-50 °C if we add LDA in one portion. However, no
phthalocyanine was formed while LDA was added dropwise.
This difference could be attributed to the heat derived from
instantaneous mixing of phthalonitrile and LDA.
Reaction time is an important factor for phthalocyanine
synthesis. To get higher yield of phthalocyanine, longer time is
generally required. Table 3 lists the yields of the reaction
proceeded at 25 °C for different time from 10 minutes to 20
hours. The reaction of 10 min can offer a yield of 37.1 %.
Prolonging the reaction does not significantly improve the yield.
the most widely utilized amide base for the deprotonation of
weakly acidic organic compounds. As proved in the systematic
NMR studies by Collum et al23, 24 and X-ray crystal structure
reported by Williard et al25, a dimeric THF-LDA complex is the
exclusive species of LDA in THF solution (Figure 2). The dimer
can be easily dissociated with the existence of other reactants.
Compared with alkoxide such as sodium methylate, LDA shows
stronger alkalinity. However, this base is less applied as
nucleophile for its large steric hindrance. In the reaction for
phthalocyanine synthesis, the position attacked by nucleophile is
the cyan group with a linear structure, so the steric hindrance
would not be crucial for the nucleophile attacking process.
Therefore we envisage that LDA can be a potential nucleophile
for the synthesis of phthalocyanine at low temperature.
Compared with the traditional high temperature method and
this facile method
18
some other low temperature methods,17,
shows significant advantage on terms of reaction time.
Table 1. Yields of phthalocyanine with different equivalent ratio at 25 °C for
3 hours.
Scheme 2. Structure of LDA-THF dimer and diisopropylamide anion.
eq. ratio (phthalo-
Yield/%
nitrile/LDA)
Herein, we report a novel low temperature method to
synthesize phthalocyanine by using lithium diisopropylamide as
nucleophile in THF solution. The relationships between yields to
reactant molar ratio, reaction temperature and time have been
studied in detail. By stirring phthalonitrile with equal equivalent
LDA in tetrahydrofuran at room temperature for only 10 minutes,
phthalocyanine can be obtained with yield of 37.1%. At lower
temperatures, such as -20 °C, phthacyanine can also be obtained
with a moderate yield. Mechanism of this low temperature
process was rationalized by density functional theory (DFT)
calculations. Moreover, this method is also efficient for the
synthesis of substituent pahthalocyanines from some
phthalonitrile derivatives.
1 : 0.2
1 : 0.5
1 : 1
7.2
27.3
39.8
39.0
1 : 2
Table 2. Yields of phthalocyanine at different reaction temperature for 3
hours with phthalonitrile/LDA ratio of 1/1.
Yield/%
T/℃
25 (rt)
0
-20
-50
-78
39.8
19.1
13.3
2.9
0
Table 3. Yields of phthalocyanine for different reaction time with
phthalonitrile/LDA ratio of 1/1 at 25 °C.
Time
Yield/%
10 min
1 h
3 h
37.1
37.4
39.8
39.6
20 h
Scheme 3. Synthesis of phthalocyanine compounds started from
phthalonitrile and LDA.
With the presence of LDA, the formation of phthalocyanine
from phthalonitrile in THF can take place at 25 °C after reacting
for 3 hours. As shown in Table 1, the amount of LDA has a
remarkable influence on the reaction. The change in molar ratio
of phthalonitrile/LDA from 1:0.2 to 1:2 resulted in yields
improvement from 7.2 % to 39.8 %. The yields with molar ratio
of 1:1 and 1:2 are almost the same, indicating that the LDA is
“saturated” to phthalonitrile with molar ratio of 1:1. In
comparison with the other methods using Na or Li alcoholate
base, the required amount of base (LDA) in our methos is
significantly reduced.18, 19 This is due to LDA can be more easily
dissociated into anions as compared to alkoxides. Decreasing the
amount of base or nucleophile will not only save raw material,
but also reduce the possibility of side reaction.
Scheme 4. Mechanism of phthalocyanine’s formation with diisopropylamide
anion as nucleophile
Under the same molar ratio of reactants, we also performed the
reaction at different temperature. The yields of phthalocyanine
with the same amount of phthalonitrile and LDA at various
temperatures were summarized in Table 2. These results indicate
The possible mechanism for the formation of phthalocyanine
in our method was shown in Scheme 4. With the existence of

reactant (phthalonitrile), LDA could dissociate to provide
numerous diisopropylamide anions, which plays a key role as
nucleophile to attack cyan group on phthalonitrile. This process
leads to the formation of intermediate IM-1, through which
isoindolyl moiety IM-2 can be obtained from an intra-molecular
reaction. After further nucleophilic reaction, cyclization,
reduction and acidification process, the phthalocyanine could be
finally obtained. This process is similar to the mechanism with
RO- as nucleophile (Scheme 1).
To verify this mechanism, DFT calculation was performed to
obtain the energies of intermediates and transition states. As
shown in Figure 1 and Table 4, activation energy of the reaction
is only 13.16 kcal/mol. Generally, reaction with activation energy
less than ca. 20 kcal/mol could be regarded as accessible at room
temperature. Therefore, the formation of phthalocyanine at
ambient or even lower temperature is reasonable due to the low
activation energy.
phthalonitrile with 1 equivalent lithium diisopropylamide (LDA)
in tetrahydrofuran at room temperature for only 10 minutes, the
phthalocyanine can be obtained in 37.1% yield. This process is
facile and low reactant-consuming in comparison with reported
work at low temperature. The mechanism of LDA attacking cyan
to initiate the reaction has been rationalized by DFT calculations.
Meanwhile, this method can be further utilized for synthesizing
some phthalonitrile derivatives with nucleophilic stable
substituents, leading to potential applications in other kinds of
functional derivatives.
Table 5. Yileds of phthalocyanine products. (reaction conditions: molar ratio
= 1/1, 25 °C, 3 h)
Phthalonitrile
Pthalocyanine (Yield/%)
PcH2 (39.8)
TS-1
4-tBu-PcH2 (16.7)
TS-2
IM-2
No product
IM-1
Reactants
4-S-tBu-PcH2 (27.0)
No product
Figure 1. Free energy (G) of reactants, transition states and intermediates.
Table 4. Free energy (G) and electronic energy (E) of reactants, transition
states and intermediates.
G*(kcal/mol)
0
E*(kcal/mol)
0
4,4’-bis-S-tBu-PcH2(19.2)
Reactants
TS-1
13.160
6.630
9.017
8.057
8.732
IM-1
-1.531
-0.323
-1.399
Acknowledgments
TS-2
This work was financially supported by the Major State Basic
Research Development Program (Grant Nos. 2011CB808704,
2013CB922100, and 2011CB933300), and Doctoral Fund of
Ministry of Education of China (20120091130002).
IM-2
*Structures optimized and energies calculated under B3LYP/6-
31G* method.
Our method could also be used to synthesize phthalocyanine
compounds with substituents. We selected several phthalonitrile
derivatives and tried to obtain the corresponding phthalocyanines.
As shown in Table 5, phthalonitrile with tertbutyl or tertbutyl
thiol could be successfully transformed to phthalocyanine, while
no green or blue products were obtained from dichloro- or nitro-
phthalonitrile. This result could be attributed to different stability
of these substituents with the existence of nucleophile. It is
difficult for alkyl or alkyl thiol groups to be attacked by
nucleophile. However, chloride in aromatic ring could be easily
substituted by diisopropylamide anion.26 Meanwhile, the nitrogen
atom of nitro can also be easily attacked by nucleophile. These
side reactions will replace the cyan group attacking process and
result in no cyclization product.
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Supplementary Material
Detailed procedure for synthesis of phthalonitrile derivatives and
phthalocyanine compounds ocould been found in supplementary
material.

Graphical Abstract
Facile synthesis of phthalocyanine at low
temperature with diisopropylamide anion as
nucleophile
Wei Zheng, Cheng-Zhang Wan, Jing-Xuan Zhang, Cheng-Hui Li*, Xiao-Zeng You ∗