First divergent strategy using two AB2 unprotected monomers for the rapid synthesis of dendrimers [2]

Full text of DOI:10.1021/ja0029228

6698
J. Am. Chem. Soc. 2001, 123, 6698-6699
Scheme 1
First Divergent Strategy Using Two AB2 Unprotected
Monomers for the Rapid Synthesis of Dendrimers
Laurent Brauge, Germinal Magro,
Anne-Marie Caminade,* and Jean-Pierre Majoral*
Laboratoire de Chimie de Coordination
CNRS, 205 route de Narbonne
31077 Toulouse Cedex 4, France
ReceiVed August 7, 2000
Dendrimers and dendritic molecules1 offer a fascinating palette
of very unique properties, with applications in numerous fields
ranging from chemistry, catalysis, or material sciences to biology.
However, their synthesis is tedious, due to the large number of
steps needed to grow these macromolecules. Several ways have
been proposed to accelerate the synthesis by diminishing the
number of steps. The first one, often called “double-stage”,2
implies the grafting of dendrons to the surface of small dendrimers
called “hypercores”. However, the total number of reactions used
to obtain the dendron and the hypercore is the same as for the
simple step-by-step synthesis of the final dendrimer. A second
type of method used to improve the synthesis of dendrimers is
called “double exponential growth”.3 In this case, the growing
of the dendron occurs bidirectionally (periphery and focal point).
This type of strategy could be interesting for the rapid synthesis
of high-generation dendrimers, but it has been experienced only
for middle-sized dendrons, leading, for instance, to a fourth
generation dendron in seven steps (instead of eight by a classical
way). A third way to accelerate the synthesis of dendrimers
consists of using hypermonomers;4 this means compounds of type
AB4 or AB8 instead of the AB2 or AB3 monomers classically
used in dendrimer chemistry. This strategy increases rapidly the
number of end groups, but it does not improve the number of
steps needed to obtain one generation (generally 2). Finally, a
fourth method called “orthogonal coupling strategy”5 consists of
using two types of AB2 units, which contain two pairs of
complementary coupling functionalities. This type of “orthogonal
system” implies a set of completely independent class of
protecting groups.6 Thus, in all cases at least one of these functions
needs to be activated using another reagent, which of course
generates byproducts, implying purification at each step. However,
this strategy designed for the convergent synthesis of dendrons
is powerful since it gives a new generation at each step. To the
best of our knowledge, this type of strategy has never been applied
to a divergent synthesis of dendrimers, or to two pairs of com-
plementary functions able to react spontaneously without any
activating agent. This last point appears highly desirable, since it
could theoretically allow the growing of dendrimers without
purification, provided each reaction is chosen to be quantitative.
In the course of our researches concerning the synthesis of
phosphorus-containing dendrimers, we have demonstrated that the
condensation reaction between phosphorhydrazides and aldehydes7
on one side, and the Staudinger reaction between phosphines and
azides8 on the other side, possess both properties. Indeed, these
reactions are quantitative; there is no need for an activating agent,
and the byproducts are only water for the condensation and
nitrogen for the Staudinger reaction. Having in hand these
reactions, the goal was to design two types of AB2 monomers,
one with aldehyde and azide functions, the other one with
hydrazine and phosphine functions. The later one is obtained in
(1) For reviews, see for example: (a) Tomalia, D. A.; Naylor, A. M.;
Goddard, W. A., III. Angew. Chem., Int. Ed. Engl. 1990, 29, 138. (b) Tomalia,
D. A.; Durst, H. D. In Topics in Current Chemistry; Weber, E., Ed.;
Supramolecular Chemistry I, Vol. 165; Springer-Verlag: Berlin, 1993; pp
193-313. (c) Newkome, G. R.; Moorefield, C. N.; Vo¨gtle, F. In Dendritic
Molecules; VCH: Weinheim Germany, 1996. (d) Zeng, F.; Zimmerman, S.
C. Chem. ReV. 1997, 97, 1681. (e) Archut, A.; Vo¨gtle, F. Chem. Soc. ReV.
1998, 27, 233. (f) Chow, H. F.; Mong, T. K. K.; Nongrum, M. F.; Wan, C.
W. Tetrahedron 1998, 54, 8543. (g) Fischer, M.; Vo¨gtle, F. Angew. Chem.,
Int. Ed. 1999, 38, 884. (h) Bosman, A. W.; Janssen, H. M.; Meijer, E. W.
Chem. ReV. 1999, 99, 1665. (i) Majoral J. P.; Caminade A. M. Chem. ReV.
1999, 99, 845.
(2) (a) Wooley, K. L.; Hawker, C. J.; Fre´chet, J. M. J. J. Am. Chem. Soc.
1991, 113, 4252. (b) Miller, T. M.; Neenan, T. X.; Zayas, R.; Bair, H. E. J.
Am. Chem. Soc. 1992, 114, 1018. (c) Xu, Z. F.; Kahr, M.; Walker, K. L.;
Wilkins, C. L.; Moore, J. S. J. Am. Chem. Soc. 1994, 116, 4537. (d) Ihre, H.;
Hult, A.; Fre´chet, J. M. J.; Gitsov, I. Macromolecules 1998, 31, 4061. (e)
Forier, B.; Dehaen, W. Tetrahedron 1999, 55, 9829. (f) Maraval, V.; Laurent,
R.; Donnadieu, B.; Mauzac, M.; Caminade, A. M.; Majoral, J. P. J. Am. Chem.
Soc. 2000, 122, 2499.
(3) (a) Kawaguchi, T.; Walker, K. L.; Wilkins, C. L.; Moore, J. S. J. Am.
Chem. Soc. 1995, 117, 2159. (b) Chang, H. T.; Chen, C. T.; Kondo, T.;
Siuzdak, G.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996, 35, 182. (c)
Klopsch, R.; Franke, P.; Schlu¨ter, A. D. Chem. Eur. J. 1996, 2, 1330. (d)
Ashton, P. R.; Anderson, D. W.; Brown, C. L.; Shipway, A. N.; Stoddart, J.
F.; Tolley, M. S. Chem. Eur. J. 1998, 4, 781.
(4) (a) Wooley, K. L.; Hawker, C. J.; Fre´chet, J. M. J. Angew. Chem., Int.
Ed. Engl. 1994, 33, 82. (b) Twyman, L. J.; Beezer, A. E.; Mitchell, J. C. J.
Chem. Soc., Perkin Trans. 1 1994, 407. (c) L’abbe´, G.; Forier, B.; Dehaen,
W. Chem. Commun. 1996, 2143. (d) Ohta, M.; Fre´chet, J. M. J. J. Macromol.
Sci. Pure Appl. Chem. 1997, A34, 2025. (e) Bo, Z. S.; Zhang, X.; Zhang, C.
M.; Wang, Z. Q.; Yang, M. L.; Shen, J. C.; Ji, Y. P. J. Chem. Soc., Perkin
Trans. 1 1997, 2931. (f) Morgenroth, F.; Berresheim, A. J.; Wagner, M.;
Mu¨llen, K. Chem. Commun. 1998, 1139. (g) Wiesler, U. M.; Mu¨llen, K. Chem.
Commun. 1999, 2293. (h) Gilat, S. L.; Adronov, A.; Fre´chet, J. M. J. J. Org.
Chem. 1999, 64, 7474. (i) Scott, D. A.; Kru¨lle, T. M.; Finn, M.; Fleet, G. W.
J. Tetrahedron Lett. 2000, 3959.
9
two steps from P(S)Cl3. Two equivalents of NaOC6H4PPh2 are
first reacted at low temperature to yield ClP(S)(OC6H4PPh2)2. A
(5) (a) Spindler, R.; Fre´chet, J. M. J. J. Chem. Soc., Perkin Trans. 1 1993,
913. (b) Xu, Z.; Moore, J. S. Angew. Chem., Int. Ed. Engl. 1993, 32, 1354.
(c) Zeng, F. W.; Zimmerman, S. C. J. Am. Chem. Soc. 1996, 118, 5326. (d)
Deb, S. K.; Maddux, T. M.; Yu, L. P. J. Am. Chem. Soc. 1997, 119, 9079. (e)
Deb, S. K.; Maddux, T. M.; Yu, L. P. Polym. Mater. Sci. Eng. 1997, 77, 163.
(f) Klopsch, R.; Koch, S.; Schlu¨ter, A. D. Eur. J. Org. Chem. 1998, 1275, 5.
(g) Ingerl, A.; Neubert, I.; Klopsch, R.; Schlu¨ter, A. D. Eur. J. Org. Chem.
1998, 2551, 1. (h) Freeman, A. W.; Fre´chet, J. M. J. Org. Lett. 1999, 1, 685.
(i) Ishida, Y.; Jikei, M.; Kakimoto, M. Macromolecules 2000, 33, 3202.
(6) Barany, G.; Merrifield, R. B. J. Am. Chem. Soc. 1977, 99, 7363.
(7) (a) Launay, N.; Caminade, A. M.; Lahana, R.; Majoral, J. P. Angew.
Chem., Int. Ed. Engl. 1994, 33, 1589. (b) Launay, N.; Caminade, A. M.;
Majoral, J. P. J. Am. Chem. Soc. 1995, 117, 3282. (c) Slany, M.; Bardaj´ı, M.;
Casanove, M. J.; Caminade, A. M.; Majoral, J. P.; Chaudret, B. J. Am. Chem.
Soc. 1995, 117, 9764. (d) Lartigue, M. L.; Donnadieu, B.; Galliot, C.;
Caminade, A. M.; Majoral, J. P.; Fayet, J. P. Macromolecules 1997, 30, 7335.
(8) (a) Galliot, C.; Pre´voˆte´, D.; Caminade, A. M.; Majoral, J. P. J. Am.
Chem. Soc. 1995, 117, 5470. (b) Maraval, V.; Laurent, R.; Donnadieu, B.;
Mauzac, M.; Caminade, A. M.; Majoral, J. P. J. Am Chem. Soc. 2000, 122,
2499. (c) Sebastian, R. M.; Magro, G.; Caminade, A. M.; Majoral, J. P.
Tetrahedron 2000, 56, 6269.
(9) Merino, S.; Brauge, L.; Caminade, A. M.; Majoral, J. P.; Taton, D.;
Gnanou, Y. Chem. Eur. J. 2001. Accepted for publication.
10.1021/ja0029228 CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/19/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 27, 2001 6699
second reaction with methyl hydrazine affords H2NNMeP(S)-
(OC6H4PPh2)2 1, an AB2 type compound with A ) NH2 and
B ) PPh2. The second type of molecule should have A ) N3
and B ) CHO. Compound 2 (N3P(S)(OC6H4CHO)2)10 perfectly
fits these requirements. However, the reaction between compounds
1 and 2 would lead to an hyperbranched polymer; to avoid this
situation, and to grow a dendrimer in a divergent way, one has
to react, first, one of the AB2 monomers with a core, to deactivate
7
its A function. We choose to use (S)P(OC6H4CHO)3 G0 as a
core. Thus, the first step is the condensation reaction between
G0 and 3 equiv of the AB2 monomer 1 (Scheme 1). The first
generation G1, having six diphenylphosphino end groups is easily
obtained. The next step is the Staudinger reaction between G1
and 6 equiv of the azide 2, which affords the second generation
G2 (12 aldehyde end groups). The dendrimer is then grown using
again monomer 1, then monomer 2 (Scheme 1). Thus, the
formation of the fourth generation G4 having 48 aldehyde end
groups, necessitates only four steps from the core G0. 1H and 13
C
NMR give good evidence for the completion of reactions, but
31P NMR appears to be the most powerful technique for this
purpose. Indeed, the condensation reaction induces the shielding
of the signal of the PdS group of the phosphorhydrazide 1 from
δ ) 67.0 to 61.6 (for G1) or 61.9 (for G3) ppm, whereas the
Staudinger reaction induces the appearance of a set of two
doublets at δ ) 14.3 (PdN) and δ ) 50.2 ppm (PdS).
Furthermore, the narrow polydispersity of all compounds has been
checked by size exclusion chromatography, which gives very
narrow peaks for G2 and G4 (see Supporting Information). The
enlargement observed for G3 is presumably due to oxidation of
the phosphine end groups during the analysis or interactions of
the phosphine with the column.9
Figure 1. 31P NMR spectra of dendrimers G4 step-by-step and G4
The compounds obtained are layered dendrimers made of
O-C6H4-Z-P(S) linkages, the difference between two layers being
the nature of Z, CHdN-N(Me) or Ph2PdN groups. The presence
of PdN-PdS groups is particularly interesting since we have
already demonstrated their specific reactivity with electrophiles,
which opened large avenues for the obtaining of dendritic
structures having very original architectures.11 Furthermore,
compounds 1 and 2 could be used also in a convergent strategy,
provided the B functions of one of them could be deactivated in
a first step. Deactivation of phosphino groups in 1 can be
performed by oxidation, sulfuration, or complexation, while
deactivation of aldehyde groups in 2 can be done, that is, by a
Schiff reaction involving Girard P or T reagents.12
In fact, the type of synthesis we propose here is not stricto
sensus an orthogonal system since no deprotection of both AB2
monomers is required, but this particularity offers a marked
advantage over previously reported systems. Indeed, it is clear
that with a strict control of the stoichiometry, this sequence of
reactions does not require any isolation, since the only byproducts
one-pot.
are H2O and N2. Thus, we have tried to carry out a one-pot
experiment to obtain directly the fourth generation starting from
the core. Two aspects of the synthesis require a particular care:
(i) this type of synthesis necessitates a strict control of the
stoichiometry, (ii) we observed that the condensation step is
slower during the one-pot process; thus, it is advisable to
concentrate the solution before adding 1. The spectroscopic
characteristics of G4 obtained by the one-pot process are very
similar to those described for G4 obtained step-by-step. However,
a slight broadening of the peaks is detectable in 31P NMR (Figure
1), as well as for SEC traces. A very small peak at a higher
retention time indicates that a slight excess of one reagent was
used at one step, leading to the formation of a small dendrimer.
The slight broadening of the base of the main peak corresponds
to uncompleted reactions of G4.
To the best of our knowledge, this is the first example of the
one-pot synthesis of a fourth generation dendrimer obtained rather
cleanly. The easy obtaining of such a compound opens the way
to a broad range of reactivity.
(10) Mitjaville, J.; Caminade, A. M.; Daran, J. C.; Donnadieu, B.; Majoral,
J. P. J. Am. Chem. Soc. 1995, 117, 1712.
(11) (a) Larre´, C.; Caminade, A. M.; Majoral, J. P. Angew. Chem., Int. Ed.
Engl. 1997, 36, 596. (b) Galliot, C.; Larre´, C.; Caminade, A. M.; Majoral, J.
P. Science 1997, 277, 1981. (c) Larre´, C.; Donnadieu, B.; Caminade, A. M.;
Majoral, J. P. J. Am. Chem. Soc. 1998, 120, 4029. (d) Larre´, C.; Bressolles,
D.; Turrin, C.; Donnadieu, B.; Caminade, A. M.; Majoral, J. P. J. Am. Chem.
Soc. 1998, 120, 13070.
(12) Marmillon, C.; Gauffre, F.; Gulik-Krzywicki, T.; Loup, C.; Caminade,
A. M.; Majoral, J. P.; Vors, J. P.; Rump, E. Angew. Chem., Int. Ed. Engl.
2001. Accepted for publication.
Supporting Information Available: Experimental details of syn-
theses; 31P, 1H, 13C NMR, IR, elemental analyses data, 31P NMR spectra
for G1, G2, G3, G4, and G4 one-pot; numbering scheme used for NMR;
expanded formulas of G4; SEC traces for dendimers G2, G3, G4, and G4
one-pot (PDF). This material is available free of charge via the Internet
at http://pubs.acs.org.
JA0029228