Synthesis of on resin poly(propylene imine) dendrimer and its use as organocatalyst

Article abstract of DOI:10.1016/j.tetlet.2014.02.084

Solid phase synthesis of poly(propylene imine) dendrimer is described. An iterative synthesis including double Michael addition of acrylonitrile to the primary amino groups on crosslinked polystyrene support followed by reduction of nitrile groups to amin

Full text of DOI:10.1016/j.tetlet.2014.02.084

Tetrahedron Letters 55 (2014) 2352–2354
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of on resin poly(propylene imine) dendrimer and its use
as organocatalyst
a,
Rajesh Krishnan Gopalakrishna Panicker a,b, , Sreekumar Krishnapillai
⇑
⇑
a Department of Applied Chemistry, Cochin University of Science and Technology, Cochin, Kerala 682022, India
b Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, NY 14260, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Solid phase synthesis of poly(propylene imine) dendrimer is described. An iterative synthesis including
double Michael addition of acrylonitrile to the primary amino groups on crosslinked polystyrene support
followed by reduction of nitrile groups to amino groups give poly(propylene imine) dendrimers up to
third generation attached to the polystyrene support. The supported dendrimer is used as an organocat-
alyst to Knoevenagel condensations. The supported catalyst showed good selectivity and the product was
obtained in excellent yield under green reaction conditions. Densely packed amino groups enhance catal-
ysis by a co-operative effect. The catalyst is recoverable and reusable.
Received 10 December 2013
Revised 20 February 2014
Accepted 24 February 2014
Available online 1 March 2014
Keywords:
Solid phase synthesis
Dendrimer
Ó 2014 Elsevier Ltd. All rights reserved.
Poly(propylene imine)
Knoevenagel condensation
Organocatalysis
Dendrimers are considered as the fourth generation of macro-
molecule architecture and these macromolecules have potential
applications in chemistry, material science, and biology.1,2 Conver-
gent and divergent methods are the two general strategies em-
ployed in the synthesis of dendrimers and both these methods
have their own merits and demerits.3 Details of dendrimer synthe-
sis and their applications are well documented in many books and
reviews.1–3 Generally dendrimer synthesis is performed in solution
phase. Incomplete reactions and side reactions are two inherent
problems associated with dendrimer synthesis and magnitude of
these problems increases when dendrimer synthesis is performed
on solid phase. It requires great efforts to optimize reaction condi-
tions to eliminate these problems and because of this, there are
only few reports on solid phase dendrimer synthesis.4,5 Dendri-
mers attached to insoluble supports have potential applications
in catalysis, as nanomaterials and in biotechnology.4,5b,6–8 Anchor-
ing of preformed or commercially available dendrimers to surfaces
via covalent bonds is another method used for immobilizing den-
drimers to insoluble materials.8a,b,9 This strategy is synthetically
demanding mainly because of the complex architecture of dendri-
mers and their high cost. In this context, a well optimized solid
phase synthesis protocol is more appealing to immobilize dendri-
mers on insoluble materials.
Solid phase syntheses of many dendrimers including poly(amido
amine), poly(aryl ether), and poly(proline) are already reported in
the literature.4,5 Even-though poly(propylene imine) (PPI) dendri-
mer is the first major class of dendrimers synthesized in solution,
their solid phase synthesis remained a challenge because of the
drastic reaction conditions like multiple catalytic or metal hydride
reductions used in the synthesis. On the other hand preformed PPI
dendrimers were grafted on solid supports for various applica-
tions.9 Here we report a general strategy for solid phase synthesis
of PPI dendrimers. We used lightly crosslinked polystyrene as solid
support for optimizing the reaction conditions. But to show the
generality of this solid phase synthesis PPI dendrimers were also
synthesized on Merrifield’s resin and divinylbenzene crosslinked
poly(methyl methacrylate) resins using the optimized conditions.
Since the supported PPI dendrimer contains multiple primary
and tertiary amino groups it can act as reusable organocatalyst
and this was shown by using it as a heterogeneous catalyst in
the synthesis of
a,b unsaturated nitrile compounds by Knoevena-
gel condensation. Organocatalysis by dendrimers is important be-
cause of the ability of dendrimers to mimic enzymes in size and
shape.10 Moreover, in dendrimers due to the dendritic shape, mul-
tiple catalytic sites are present in a confined space and this imparts
efficient catalysis by co-operative effects.11 These type of co-
operative effects are not usually found in single site catalysts.
Moreover dendrimers immobilized to insoluble supports are easy
to separate from the final reaction mixture by simple filtration.
Another advantage of the present catalyst is that it is active under
green reaction conditions and reduces the use of organic solvents.
⇑
Corresponding authors. Tel.: +1 716 645 1046; fax: +1 716 645 2207.
E-mail addresses: rajeshkr@buffalo.edu (R.K. Gopalakrishna Panicker),
drgrkrishnan@gmail.com (S. Krishnapillai).
http://dx.doi.org/10.1016/j.tetlet.2014.02.084
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

R. K. Gopalakrishna Panicker, S. Krishnapillai / Tetrahedron Letters 55 (2014) 2352–2354
2353
General method of solid phase synthesis of PPI dendrimer is
H2N
H2N
N NH2
N NH2
shown in Scheme 1. 4-Aminomethyl polystyrene 1% crosslinked
with divinyl benzene was used as the solid phase in this synthesis.
Acetic acid catalyzed double Michael additions of acrylonitrile to
the amino groups of the support results in the formation of half
generation dendrimers with nitrile surface groups and this step
is adapted from the classical synthesis of PPI dendrimer.12 Amino
groups on the supports act as both the core of the dendrimer and
the linker connecting the dendrimer to the support. Surface nitrile
groups of the half generation dendrimers were reduced to amino
groups using LiAlH4 to obtain the full generation dendrimers.
LiAlH4 is rarely exploited in solid phase synthesis because of the
difficulty in separating the side products formed during reduc-
tion.13 Newly formed amino groups of the dendrimers served as
targets of next Michael additions. Repetition of these synthetic
steps in an iterative manner results the formation of PPI dendri-
mers up to third generation attached to polystyrene support. De-
tails of synthetic procedures can be found in the Supporting
information. Since higher generation dendrimers are generally
associated with more defects, their synthesis was not attempted
at present.
Progress of solid phase synthesis was monitored using FTIR and
solid state CP–MAS-NMR spectroscopies (see Supporting informa-
tion). FTIR spectrum of aminomethyl polystyrene shows peaks cor-
responding to primary amino group and benzene ring vibrations.
Once Michael additions were complete, IR spectrum of the polymer
showed a new peak at 2244 cmÀ1 representing the C–N stretching
of the nitrile group. Moreover the peak at 3344 cmÀ1, representing
N–H stretching of amino group, disappeared completely after each
Michael addition and this proved the completion of reaction. After
LiAlH4 reduction, IR spectrum of the polymer showed the reap-
pearance of peak representing NH2 groups while the peak repre-
senting CN groups disappeared completely. Thus IR spectra
served as a proof of the progress of the solid phase synthesis. Com-
parison of solid state CP–MAS NMR spectra of the polymer before
and after reduction showed the presence and absence of the peak
at 114 ppm that represents nitrile carbon. Estimation of amino
groups and elemental analysis after each reduction step further
confirmed an exponential increase in the amount of NH2 groups at-
tached to polymer.5b As observed from the analytical data, optimi-
zation of the reaction conditions help to prevent incomplete
branching to a great extent. But the possibility of incomplete reac-
tions is not completely omitted especially in the case of dendri-
mers situated deep inside the polymer matrix and dendrimers
that are positioned very close to each other. In these cases poor
accessibility of amino groups and steric effects result in incomplete
reactions.
X
X
Y
R
CHO
R
Ethanol, r. t. 5 min
Y
X, Y- CN/COOEt, R-various substituents as
shown in table 2
Scheme 2. General method of Knoevenagel condensation catalyzed by polymer
supported PPI dendrimer.
Table 1
Influence of reaction conditions on catalysis
a,b
Entry
Catalyst loading (mol %)
Time (min)
Solvent
Yield
(%)
1
2
3
4
5
6
7
8
9
0.1
0.2
0.3
0.5
0.5
0.5
0.5
0.5
0.5
5
5
5
5
1
2
5
5
5
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Water
60
85
91
100
82
90
91
92
98
Toluene
Solventless
a
Isolated yield.
b
5 mmol of benzaldehyde, 5 mmol malononitrile, 5 mL of solvent, room
temperature.
can act as efficient organocatalysts due to the co-operative effect
between them due to the dendritic structure. To show this, the
supported PPI dendrimers were used as organocatalysts in Knoeve-
nagel condensations between carbonyl compound and active
hydrogen compounds (Scheme 2). Knoevenagel condensation is a
synthetically important reaction both in chemistry and in material
science. This reaction is widely used in the synthesis of natural
products, biologically important molecules, and photonic materi-
als.14 A number of catalysts including polymer supported ones
were investigated in this reaction.15
Originally a model reaction between benzaldehyde and malon-
onitrile was used to optimize reaction conditions like solvent, cat-
alyst concentration, and reaction time. The results are summarized
in Table 1. As shown in the table only 0.5 mol % of the catalyst is
required to promote the model reaction in 5 min and the yield of
the product is 100%. The catalyst can easily be separated from
the reaction mixture by simple filtration and washing with ethanol
(see Supporting information). The reaction can be performed under
solventless conditions as well as in green solvents like water and
ethanol.
Polymer supported PPI dendrimers have multiple primary and
tertiary amino groups that are closely packed to each other due
to the dendritic structure. These closely packed amino groups
Generality of the catalyst was further proved by synthesizing a
number of a,b-unsaturated nitriles using substrates with different
substitution patterns. The results are summarized in Table 2. As
NH2
H2N
H2N
NH2
NH2
N
N
NH2
N
N
1. Acrylonitrile,
Ac.Acid
NH2
NH2
R. T. 3 days
NH2
N
N
2. LiAlH4, THF
0-50 oC, 12h
N
N
NH2
NH2
Scheme 1. General method of solid phase synthesis of poly(propylene imine) dendrimer.

2354
R. K. Gopalakrishna Panicker, S. Krishnapillai / Tetrahedron Letters 55 (2014) 2352–2354
Table 2
Knoevenagel condensations catalyzed by polymer supported poly(propylene imine) dendrimer
Entry
Aldehyde
Active hydrogen compound
Time (min)
Yielda,b (%)
K1
K2
K3
C6H5CHO
4-CH3OC6H4CHO
4-ClC6H4CHO
CH2(CN)2
CH2(CN)2
CH2(CN)2
5
5
5
100
100
99
K4
K5
K6
K7
K8
K9
K10
K11
K12
K13
K14
K15
K16
K17
K18
K19
K20
4-(CH3)2NC6H4CHO
2-OHC6H4CHO
4-OHC6H4CHO
3-NO2C6H4CHO
4-NO2C6H4CHO
3CH3O,4-OH–C6H3CHO
3,4(CH3O)2C6H3CHO
C6H5CHO
4-CH3OC6H4CHO
4-ClC6H4CHO
4-(CH3)2NC6H4CHO
2-OHC6H4CHO
CH2(CN)2
CH2(CN)2
CH2(CN)2
CH2(CN)2
CH2(CN)2
CH2(CN)2
CH2(CN)2
(CN)CH2COOC2H5
(CN)CH2COOC2H5
(CN)CH2COOC2H5
(CN)CH2COOC2H5
(CN)CH2COOC2H5
(CN)CH2COOC2H5
(CN)CH2COOC2H5
(CN)CH2COOC2H5
(CN)CH2COOC2H5
(CN)CH2COOC2H5
5
100
98
100
98
99
99
100
100
100
98
99
100
99
10
10
10
10
5
5
5
5
10
10
10
10
15
10
10
10
4-OHC6H4CHO
3-NO2C6H4CHO
4-NO2C6H4CHO
3CH3O,4-OH–C6H3CHO
3,4(CH3O)2C6H3CHO
99
98
100
99
a
Isolated yield.
b
5 mmol of aldehyde (all are aromatic aldehydes), 5 mmol active hydrogen compound, 0.5 mol % catalyst, 5 mL ethanol, room temperature.
Heegaard, P. M. H., Eds.; Royal Society of Chemistry: UK, 2006; (d) Dendrimers
and other Dendritic Polymers; Frechet, J. M. J., Tomalia, D. A., Eds.; John Wiley &
Sons: UK, 2001.
seen in the table all the reactions were catalyzed efficiently by the
supported dendrimer. The yields of the products obtained with this
catalyst were similar to those obtained with other dendrimers and
brush polymer catalysts reported by us under same reaction condi-
tions.5b,15f But the reaction time was shorter for the present cata-
lyst compared to previous ones. This is because amino groups are
more closely packed in the present catalyst compared to the previ-
ous ones because of less flexible backbone of PPI dendrimer com-
pared to PAMAM dendrimer or the brush polymer. Moreover, the
presence of tertiary amino groups in PPI dendrimers enhances
the catalytic efficiency. But the reaction takes more time to com-
plete compared to the brush polymer catalyst under solventless
conditions. This may be due to the partial solubility of the brush
polymer in the reactants. Like many other supported catalyst this
catalyst too can be recovered by simple filtration and the recovered
catalyst was reused eight times without loss of catalytic activity.
In short, we described solid phase synthesis of poly(propylene
imine) dendrimers for the first time. The dendrimer was synthe-
sized on crosslinked polystyrene using an iterative method that in-
cludes double Michael additions of acrylonitrile to the amino
groups of polymer support followed by LiAlH4 reduction of the ni-
trile groups to amino groups. The supported dendrimer was used
as an efficient heterogeneous reusable organocatalyst in the syn-
2. (a) Lo, S. T.; Kumar, A.; Hsieh, J. T.; Sun, X. Mol. Pharm. 2013, 10, 793–812; (b)
Caminade, A.; Ouali, A.; Keller, M.; Majoral, J. Chem. Soc. Rev. 2012, 41, 4113–
4125; (c) Cheng, Y.; Zhao, L.; Li, Y.; Xu, T. Chem. Soc. Rev. 2011, 40, 2673–2703;
(d) Mintzer, M. A.; Grinstaff, M. W. Chem. Soc. Rev. 2011, 40, 173–190; (e)
Astruc, D.; Boisselier, E.; Ornelas, C. Chem. Rev. 2010, 110, 1857–1959; (f)
Twyman, L. J.; King, A. S. H.; Martin, I. K. Chem. Soc. Rev. 2002, 31, 69–82.
3. (a) Walter, M. V.; Malkoch, M. Chem. Soc. Rev. 2012, 41, 4593–4609; (b)
Grayson, S. M.; Frechet, J. M. J. Chem. Rev. 2001, 101, 3819–3868.
4. (a) Kehat, T.; Goren, K.; Portnoy, M. New J. Chem. 2007, 31, 1218–1242; (b)
Dahan, A.; Portnoy, M. J. Polym. Sci. Polym. Chem. 2004, 43, 235–262; (c)
Lebreton, S.; Monaghan, S.; Bradley, M. Aldrichim. Acta 2001, 34, 75–83.
5. (a) Huang, A. Y.; Tsai, C. H.; Chen, H. Y.; Chen, H. T.; Lu, C. Y.; Lin, Y. T.; Kao, C. L.
Chem. Commun. 2013, 5784–5786; (b) Krishnan, G. R.; Sreekumar, K. Eur. J. Org.
Chem. 2008, 4763–4768; (c) Sanclimens, G.; Crespo, L.; Giralt, E.; Royo, M.;
Albericio, F. Biopolymers 2004, 76, 283–297; (d) Dahan, A.; Portnoy, M.
Macromolecules 2003, 36, 1034–1038; (e) Basso, A.; Evans, B.; Pegg, N.;
Bradley, M. Chem. Commun. 2001, 697–698.
6. (a) Krishnan, G. R.; Sreekumar, K. Polymer 2008, 49, 5233–5240; (b) Krishnan,
G. R.; Sreekumar, K. Appl. Catal. A 2009, 353, 80–86; (c) Berget, P. E.; Teixeira, J.
M.; Jacobsen, J. L.; Schore, N. E. Tetrahedron Lett. 2007, 48, 8101–8103; (d)
Dahan, A.; Portnoy, M. Org. Lett. 2003, 5, 1197–1200.
7. (a) Xu, Y.; Zhang, Z.; Zheng, J.; Du, Q.; Li, Y. Appl. Organometal. Chem. 2013, 27,
13–18; (b) Krishnan, G. R.; Sreekumar, K. Soft Mater. 2010, 8, 114–129.
8. (a) Matsushita, T.; Handa, S.; Naruchi, K.; Garcia-Martin, F.; Hinou, H.;
Nishimura, S. I. Polym. J. 2013, 45, 854–862; (b) Hameau, A.; Colliere, V.;
Grimoud, J.; Fau, P.; Rogues, C.; Caminade, A.; Turrin, C. RSC Adv. 2013, 3,
19015–19026; (c) Siyad, M. A.; Kumar, G. S. V. Org. Biomol. Chem. 2013, 11,
4860–4870.
thesis of a,b-unsaturated nitriles under green reaction conditions.
9. Murugan, E.; Rangasamy, R. J. Polym. Sci. Polym. Chem. 2010, 48, 2525–2532.
10. Liang, C.; Frechet, J. M. J. Prog. Polym. Sci. 2005, 30, 385–402.
Acknowledgements
11. (a) Helms, B.; Frechet, J. M. J. Adv. Synth. Catal. 2006, 348, 1125–1148; (b)
Sarkar, A.; Ilankumaran, P.; Kisanga, P.; Verkade, J. G. Adv. Synth. Catal. 2004,
346, 1093–1096.
The authors acknowledge Defense Research and Development
Organization, India for financial support.
12. Buchleier, E.; Wehner, W.; Vogtle, F. Synthesis 1978, 155–158.
13. Gooding, O. W.; Baudart, S.; Deegan, T. L.; Heisler, K.; Labadie, J. W.; Newcomb,
W. S.; van Porco, J. A.; Eikeren, P. J. Comb. Chem. 1999, 1, 113–122.
14. (a) Kusakabe, T.; Kawai, Y.; Kato, K. Org. Lett. 2013, 15(5102), 5105; (b)
Singjunla, Y.; Baudoux, J.; Rouden, J. Org. Lett. 2013, 15, 5770–5773; (c) Zhu, E.;
Hai, J.; Wang, Z.; Ni, B.; Jiang, Y.; Bian, L.; Zhang, F.; Tang, W. J. Phys. Chem. C
2013, 117, 24700–24709; (d) Zhao, Y.; Huang, C.; Kim, M.; Wong, B. M.;
Leonard, F.; Gopalan, P.; Eriksson, M. A. ACS Appl. Mater. Interfaces 2013, 5,
9355–9361; (e) Ranise, A.; Lucchesini, F.; Cavigila, M.; Alfei, S.; Spallarossa, A.;
Caneva, C. Tetrahedron 2013, 69, 10858–10868.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
02.084.
15. (a) Le, W. J.; Lu, W. F.; Zhou, J. T.; Cheng, H. L.; Gao, Y. H. Tetrahedron Lett. 2013,
54, 5370–5373; (b) Li, G. W.; Xiao, J.; Zhang, W. Q. Chin. Chem. Lett. 2013, 24,
52–54; (c) Zhao, J.; Xie, J.; Au, C. T.; Yin, S. F. Appl. Catal. A 2013, 467, 33–37; (d)
Xu, J.; Shen, K.; Xue, B.; Li, Y. X. J. Mol. Catal. A 2013, 372, 105–113; (e) Mangala,
K.; Sreekumar, K. Appl. Organomet. Chem. 2013, 27, 73–78; (f) Krishnan, G. R.;
Niveditha, K. S.; Sreekumar, K. Ind. J. Chem. B 2013, 52B, 428–431.
References and notes
1. (a) Dendrimer Chemistry; Vogtle, F., Richardt, G., Werner, N., Eds.; Wiley-VCH:
Weinheim, 2009; (b) Designing Dendrimers; Campagna, S., Ceroni, P.,
Puntoriero, F., Eds.; John Wiley & Sons: Hoboken, 2012; (c) Dendrimers in
Medicine and Biotechnology: New Molecular Tools; Boas, U., Christensen, J. B.,