In the Classroom
Dendrimers: Branching Out of Polymer Chemistry Eric E. Simanek* and Sergio O. Gonzalez Department of Chemistry, Texas A&M University, College Station, TX 77843-3255; *
[email protected] What are dendrimers? Why are these molecules receiving so much attention? Intended for undergraduate students of organic chemistry, this article addresses synthetic concepts surrounding dendrimers including the use of protecting groups, functional group interconversions, and convergent and divergent synthetic strategies. The review concludes with some of the elementary synthetic transformations used to construct dendrimers. Polymer chemistry is branching out—literally! Linear polymers, including polyamides such as nylon and Kevlar, polyolefins such as polyethylene and polystyrene, and polyesters such as rayon and dacron, are now being joined by new classes of branched polymers including perfectly branched structures called dendrimers. Over the last ten years, dendrimers
Periphery
2 1 Core A B
* B
B HO OH
HO HO
B HO
O
HOHO
HN
HO NH
HO
B OH OH HO OH
N H
* A
O
HO
NH O
O
O
NH
O
OH OH OH
NH O HN
O HO
O
O
HN HO HO
HN
O
O
OH
OH OH
Core
OH OH
OH OH
Figure 1. The dendrimers of Moore and Newkome invoke images of snowflakes and trees. Moore uses an AB2 monomer at the branching group (*), while Newkome uses an AB 3 monomer. Both dendrimers are G2 dendrimers.
1222
have attracted significant attention, and have been the subject of numerous reviews (1–4). Etiologically, dendrimer is derived from the Greek word for tree (dendron) and the scientific suffix for unit (mer, as in polymer). Other names that attempt to embody the shapes of these molecules include arborols and cascade or starburst polymers. Figure 1 shows dendrimers described by Moore (5) and Newkome (6). Moore’s phenylacetylene dendrimers reflect the snowflake-like perfection of these molecules. Like all fields, dendrimer chemistry has developed its own jargon. The central unit of a dendrimer is referred to as the core. Groups on the edges are referred to as peripheral groups. The size of a dendrimer is reflected by its generation, a number that can be calculated by counting the number of repeat units required to travel from the core of the dendrimer to a group on the periphery. The phenylacetylene dendrimer shown is a generation-two dendrimer, G2, because two phenylacetylene groups must be crossed to arrive at the edge of the central benzene ring. Calculating the generation number for Newkome’s architecture depends greatly on one’s definition of a repeat unit. Many would consider this polymer to be a G2 dendrimer. Although both of these dendrimers are G2, Newkome’s appears to be more dense with regard to the number of atoms. This variation is the result of the chosen building blocks. Moore uses an AB2 building block, while Newkome uses an AB3 building block. This nomenclature is straightforward: A refers to the number of bonds coming into a branching group (almost always one) from the core, B refers to the number of bonds leaving a branching group towards the periphery (most commonly two through five). In Moore’s dendrimer, we choose the benzene ring labeled with an asterisk as the branching group and see that one alkyne comes into it from the core, and two alkynes leave it toward the periphery, hence A1B2 or AB2. We can define Newkome’s branching group a number of ways, but the easiest is to choose the carbon atom labeled with an asterisk. One carbon–carbon bond comes into this branching group from the core while three carbon–carbon bonds radiate from it towards the periphery, hence A1B3 or AB3. With some imagination (and without violating the octet rule) one can design a number of AxBy systems. The other distinction between these two G2 dendrimers is that Newkome’s construction conjures the image of a tree, albeit of molecular dimensions. The best way to calibrate oneself to the size of these molecules and molecular dimensions is to use a logarithmic scale relating the sizes of familiar objects at factors of ten (see Fig. 2). The differences between the height of the authors (less than 2 m) and the diameter of a human hair (0.1 mm) are comfortable units and many everyday items can be chosen to represent a decimeter, centimeter, and millimeter (the width of 10 human hairs). The length of a human cell is 10 µm. The length of a bacterium (1 µm) and the lengths of most viruses (100 nm) vary by factors of ten. The wavelength of visible light (400–700 nm) lies between the lengths of these
Journal of Chemical Education • Vol. 79 No. 10 October 2002 • JChemEd.chem.wisc.edu
100µm
10µm
10-3 m
10-4 m
10-5 m
sizes of dendrimers
Polymerize
a
limit of classical synthesis
1mm
size of features on a microchip
human cell
wavelengths of visible light
diameter of hair
n
H 2N
C-H
cholesterol
protein
virus
O
bacterium
height of author
In the Classroom
O
Polymerize
OH
H2N
O N H
OH n
b Polymerize
1m 100 m
1cm
1µm
100nm 10 nm
10-6 m 10-7 m 10-8 m
1nm
+
1Å
10-9 m 10-10 m
Figure 2. The sizes of dendrimers can be put into perspective using common objects related on a logarithmic scale.
two entities, and as such, bacteria can be observed with light microscopy while viral particles cannot. Most cellular proteins (enzymes) are ten times smaller than a virus with a diameter of 10 nm. The size of most organic molecules that are synthesized in the laboratory is 1 nm. These molecules include prescription drugs and natural products like cholesterol. The length of a carbon–hydrogen bond is 0.1 nm, or 1 Å. Dendrimers typically fall in the range of 3–10 nm in diameter. The observation that dendrimers are roughly the same size as proteins has led many researchers to engineer protein-like function into these molecules including catalysis, light harvesting, or small molecule transport. Table 1 describes areas of recent interest in some of the leading laboratories around the globe. Linear versus Branched Polymers While both linear and dendritic polymers are built up from one or more repeating units, their syntheses differ greatly. In order to be branched, one of the monomeric units of a dendrimer must have at least three sites for chemical manipulation. This prerequisite has significant synthetic implications, a challenge that is best communicated beginning with the syntheses of two slightly different linear polyamides. The monomers shown in Scheme Ia have two sites for reaction. The hands and handles correspond to nucleophilic and electrophilic groups. When this type of monomer is polymerized, the product (assuming hands can only grab handles) is a linear polymer. In Scheme Ib, a closely related polymer, nylon, can be obtained by reacting two different monomers: a molecule with two nucleophilic amine groups with a molecule with two electrophilic carboxylate groups. In both cases, the only potential side product results from cyclization of a polymer chain, an event that is disfavored at high concentrations of reactants. Simply mixing monomers or comonomers cannot be applied directly to dendrimer synthesis because polymerizing a multifunctional monomer (e.g., with one handle and two hands) leads to the formation of a wealth of different architectures (Scheme II). Only a few of these products might show the perfect snowflake-shaped targets that we described earlier. While this strategy does not yield dendrimers, it does yield a class of materials that are referred to as hyperbranched polymers. Hyperbranched polymers can display domains that are similar to dendrimers (labeled dendritic or terminal) and
n
O H2N
Polymerize
O
NH2 + HO
OH
O N H
N H
O n
Scheme I. Linear polymers are prepared by polymerizing difunctional monomer (a), or copolymerizing two suitable comonomers. (b) The resulting polyamides have slightly different structures.
Table 1. Application and Areas of Inquiry in Dendrimer Science Application Area
Reference
Catalysis Lewis Acids
7–9
Nanoclusters
10
Organometallic (C–C, C–N)
11–17
Oxidation
18
Chiral Auxillary
19
Energy Transfer Chromophores
20–23
Models of Metalloproteins
24–26
Energy Funneling
27
Redox Processes
28–30
Light Harvesting
31, 32
Photoisomerism
33, 34
New Materials/Applications New Dendritic Systems
35–40
Dendrimer–Metal Assemblies
41, 42
Supramolecular Materials
43–46
Bioconjugates/Biomaterials
47–55
Optical Materials
56–61
Gelators
62–64
Interfacial Materials
65–68
Liquid Crystals
69–71
Encapsulation, Capsules
72–78
to linear polymers (labeled linear). The ease with which hyperbranched polymers can be prepared suggests that they could serve as an economical substitute for dendrimers, but by design these reactions yield a mixture of different molecules. Dendrimer synthesis requires significantly more attention
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In the Classroom
a + polymerize
only trace amounts
linear
terminal dendritic
Scheme II. Unlike the synthesis of linear polymers, polymerizing a multifunctional monomer leads to a distribution of products governed by statistics. To prepare dendrimers alternative strategies have to be employed.
b PGM or FGI
because the synthetic chemist must exercise control over the reactions to avoid statistical mixtures of products, termed polydisperse, in order that a single product is obtained, termed monodisperse. The Role of Protecting Groups and Functional Group Interconversions Synthetic chemists exercise control over reactivity through the manipulation of protecting groups (PGM) or through functional group interconversions (FGI). Protecting groups are selectively and efficiently installed under mild conditions on the reactive group of interest rendering it unreactive. The protecting group must survive subsequent chemical steps before it is selectively and efficiently removed under mild conditions. A functional group interconversion converts the unreactive functional group to a reactive group through atom exchange (e.g., unreactive hydroxyl for reactive bromide) or oxidation–reduction chemistry (e.g., unreactive nitrile and reactive amine). Both strategies are illustrated similarly in Scheme III, using a mitten. In the absence of a mitten, mixing the two components in the appropriate ratio will lead to the desired product, but will also yield statistically larger amounts of the undesired material as illustrated in Scheme II. Instead of mixing the reactants directly, we can mask groups on one monomer, mix the components in a second step, and in a third step, unmask the groups. While this strategy clearly involves more steps and intervention on the part of the chemist, the desired material is obtained in far better yield and purity.
PGM or FGI
major product
Scheme III. Without intervention, only a trace amount of the desired material is obtained using strategy (a). Using protecting groups or functional group interconversions, the reactivity of one monomer is repressed until later in the synthesis when the reactive groups are unmasked (b). This strategy often leads to a single major product.
S PGM or FGI
S S S S
S
PGM or FGI
S
S
S
Convergent versus Divergent Syntheses Given the tree-like shape of a dendrimer, it is not surprising that two different approaches have been employed to synthesize these molecules. In the convergent approach shown in Scheme IV, synthesis begins at the surface groups, S, which are leaves by analogy, and branches are installed in an iterative fashion until the core (C, or trunk by analogy) is reached. That is, synthesis converges from the periphery to the core. The convergent approach was developed by Frechet and coworkers (79) for the syntheses of poly(arylether) dendrimers. Shown in Scheme V, two equivalents of the benzylic bromide surface group react with the phenolic groups of dihydroxybenzyl alcohol in SN2-type reactions. In the presence of a mild base, phenols are converted to more reactive phenoxide anions, while the primary alcohol is unchanged. 1224
S
S
S
S
S
S
C
C S
S S
S S
S
Scheme IV. The convergent strategy commences with the reaction of surface groups (S) with a branching group that is suitably masked. Protecting group manipulations (PGM) or functional group interconversions (FGI) provide the appropriate building block for the next step of the synthesis. This iterative process is repeated until the dendrons are reacted with a core group (C).
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In the Classroom
O HO O O
HO
O O
OH
HO
OH
HO
Br
O
K2CO3 18-Crown-6
O
K2CO3 18-Crown-6
O
O
O
X
O
O
O
O
O
O
O
O
O
O
O
O OH
X = OH
CBr4, PPh3
X = Br
O
O
O
O
O O
O
O
O
O O O
O O
O
O
HO
O
OH
O O O
O
O
O
Br
K2CO3 18-Crown-6
O O O
O O
O
O
O
OO O
O
O O
O
O O O O
O
O O
O
O
O
O O
OO
O
O
O
O O
O
O O
O
O
O
O
O O
O O
O
O
O
O
O
O
O
O
O O
O
O
O O
O
O O
O
O
O
O
O O
O O
O O
O
O O
O
O O
O O
O O
O O
O O
O O
O
O
O O
O
OH
O
O O
O
OO
O
Scheme V. Convergent syntheses were developed for the preparation of poly(arylether) dendrimers by Frechet and coworkers (79). The iterative sequence reacts two benzylic bromides with 3,5-dihydroxybenzyl alcohol. The primary alcohol is a masked bromide: a FGI using CBr4 and PPh3 leads to benzylic bromide required for subsequent elaboration.
Indeed, the primary alcohol is a masked functional group. The benzylic alcohol is transformed by FGI to a benzyl bromide. The product of these first reactions is called a first generation dendron, or D1. Larger dendrons are prepared through iteration before these dendrons are attached to the central core using similar chemistry. The functional group interconversion also involves SN2 chemistry (Scheme VI). The phosphorus atom of triphenylphosphine attacks CBr4 in an SN2 fashion liberating Br᎑ and generating a phosphonium salt, Ph3P+CBr3. This species is sufficiently electron deficient that the ordinarily unreactive primary alcohol attacks phosphorus yielding Br3C ᎑ (which ends up with the proton from the hydroxyl group). Then Br᎑ does an SN2 displacement on the benzylic carbon yielding triphenylphospine oxide (Ph3P=O), an unreactive byproduct whose formation drives the reaction to completion.
In the divergent approach, synthesis commences with the trunk, and branches are installed iteratively until, in the final step, the leaves are attached (Scheme VII). That is, synthesis diverges from the core to the periphery (80). The convergent approach is usually more labor intensive than the divergent approach, but at each stage of the convergent approach, only two molecules are required to react. The number of molecules required to react using a divergent approach increases by a factor of two (for AB2 systems) at each generation. While the divergent approach is usually easier to execute, the possibility of generating defects in the structure is greater. Early in the synthesis, monitoring the reaction is not difficult as only a small number of reactions occur, and the products and intermediates vary enough in behavior that they can be detected. At higher generations, however, when the number of reactions occurring at each step
JChemEd.chem.wisc.edu • Vol. 79 No. 10 October 2002 • Journal of Chemical Education
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In the Classroom
OH
Ph3P, CBr4
Br PGM or FGI
C
Ph3P
C
Ph3P – CBr3 + Br
Br3C – Br
C
OH
C
Ph3P – CBr3
O
S
PPh3
+
CBr3
S
S
H
S
PGM or FGI
C then
S
S O
S
PPh3
+
S
CBr3
S
H
O
O
PPh3
+
HCBr3
PPh3
+
Br
Br
+
Ph3P=O
Scheme VI. The mechanism for the FGI of alcohol to bromide involves SN2 chemistry. See text for details.
increases, monitoring the reaction is difficult. For example, 64 reactions must occur at generation five, while only 4 reactions must occur at generation two. Distinguishing products resulting from 63 and 64 reactions is not trivial. The potential for defects requires that each reaction proceeds in high yield. As a result, Michael reactions are the basis for two of the most common classes of divergentlyprepared dendrimers, the poly(propyleneimine) (PPI) of Vogtle and Meijer (Scheme VIIIa, 75), and the poly(amidoamine) (PAMAM) dendrimers of Tomalia (Scheme VIIIb, 80). In both cases, an amine nucleophile of the dendrimer attacks two Michael donors to form the tertiary amine. In the case of PPI dendrimers, the subsequent amine is masked as an unreactive nitrile that is revealed upon hydrogenation, a FGI. In the case of the PAMAM dendrimers, the esters are converted to aminoamides by reaction with ethylenediamine. While the mechanism for the hydrogenation of the nitrile is difficult to depict accurately, the transacylation reaction is best described by the standard 1226
Scheme VII. The divergent approach to dendrimers commences at the core (C) with reaction of the suitably masked building block. Protecting group manipulations (PGM) or functional group interconversions (FGI) unmask reactive groups that can be elaborated. This iterative strategy continues until the surface groups (S) are installed.
nucleophilic addition to a carbonyl group to form a tetrahedral intermediate whose collapse (with appropriate proton transfer steps) yields the desired product and methanol. One of the earliest classes of dendrimers was described by Denkwalter, who chose to use the amino acid lysine as a building block (81). Denkwalter’s synthesis is divergent, and relies on protecting group manipulations. The BOC group (–CO2C(CH3)3) is a common amine protecting group that is stable to a variety of conditions, while being labile to strong acids like trifluoroacetic acid. Of the advantages of the BOC group, the fact that it produces inert gaseous by-products upon deprotection makes it a protecting group of choice in many circumstances (Scheme IX). Choosing lysine also introduces chirality into these architectures. Other Dendrimers While the use of organometallic reagents to prepare dendrimers like those described by Moore are gaining popularity, most dendrimers are constructed using elementary reactions first introduced in undergraduate organic courses. In Scheme X, we highlight some of these reactions. This summary is by no means exhaustive, but rather is representative of the diversity in reactions being employed. The number of different types of dendrimeric architectures possible is only limited by the imagination of the chemist. Indeed, the motivated reader could undoubtedly dream and deliver a completely new class of these aesthetically pleasing architectures.
Journal of Chemical Education • Vol. 79 No. 10 October 2002 • JChemEd.chem.wisc.edu
In the Classroom
Michael Reaction Nu
H+
Nu
X
Nu
X
X
X = Electron difficient group to stabilize intemediate anion including COOR or CN
a
Poly(propyleneimine) Dendrimers N
N NH2
H 2N H 2N
Reduction
CN
4
N
NH2
CN
1. 8 N
N
N 2. Reduction
H 2N N
Next generation
NH2
N
b Poly(amidoamine) Dendrimers O 4 H2N
MeOOC
NH2
O
COOMe
OMe O
H 2N
N
NH2
H2 N
NH
NH2
NH
NH2
HN N
N
N COOMe
MeOOC
H2 N
O
HN O
Scheme VIII. Michael reactions are utilized in the divergent synthesis of two of the most studied dendrimers; poly(propyleneimine) and poly(amidoamine) dendrimers. Both nitrile and ester groups stabilize the anion resulting from addition and serve as masking groups. The nitrile (a) is reduced to a primary amine. The ester (b) is converted to an aminoamide.
O 2N
O NHBOC
O
R
N H
O
NH2 NH2
R O 2N
N H
O R
Low Reactivity with Amines. Very Stable, Long OH Shelf-life. Easily Purified.
O R
Cl
NO2
O R
High Reactivity with Amines. Unstable. Short Shelf-life. Not Easily Purified.
O
NHBOC O
NHBOC
O
HN
N H
O
OH
p-Nitrophenol groups are excellent leaving groups for making esters or amides. Unlike acid chlorides, these molecules are stable for long periods of time, and are a unique yellow so the ester cleavage can be monitored spectrophotometrically.
NHBOC
H N
NHBOC
O
=BOC O
CF3COOH CO2 +
O R
N H
NH2
H N
NH2 O
NH2 HN
NH2 O
Good Reactivity with Amines. Stable. Long Shelf-life. Easily Purified.
Scheme IX. Chiral dendrimers have been prepared divergently using BOC-protected lysine groups with an activated ester. Acylation can be monitored by with release of p-nitrophenol. Deprotection with acid unmasks amine groups for further elaboration. The gaseous (thereby separable) byproducts of BOC-deprotection make this PGM practical and a favorite of synthetic chemists.
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In the Classroom
O
Acylation Chemistry
O
+ R
Nu
X
R
O
Nu X
R
Ph H O O O OH
Ph O
a
O
H O
HO
O O
O
O H
Pd/C, H2
O O
OH
O O O O Ph H
O Ph
O H
COCl
b
Cl
R
OH OH
O
O
O Ph
+ X
Nu
O O
O O
HO HO
OH OH
R
R
N
CONH
H 2N
Cl
CONH
1) N3, DMF 2) H2, Pd/C
COCl
N
H 2N
N CONH
CONH
R
R
Wittig Reaction
O RHC PPh3 + R' C H Ylide
Ph3P O
Ph3P O
RHC C R' H
RHC C R'
Bu2N
H
Bu2N
Bu2N (Ph3)P
RHC CHR' + O PPh3
CHO
DIBAL-H
CN
CN
CHO
(Ph3)P Bu2N
Bu2N
Cl Cl Al Cl
Cl
H
Cl
Cl Al Cl
Friedel-Crafts
+ HCl + AlCl3
Cl Cl Cl
Cl
Cl
Cl Cl Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl Cl Cl Cl
AlCl3
Cl
Cl
Cl
Cl Cl
Cl
Cl
Cl Cl
ClCl Cl
Cl Cl
ClCl
Cl
Cl
Cl
Cl
Cl
Cl
1228
Cl
Cl
Cl
Cl
Cl
Cl
Cl
CHCl3 AlCl3
Cl Cl
Cl Cl
Journal of Chemical Education • Vol. 79 No. 10 October 2002 • JChemEd.chem.wisc.edu
In the Classroom
Nu
Nucleophilic Substitution Reaction Ms NH2
N Ms
N H 2N
NH2
Ms
Ms
HN
NH
N H
N
O S Me O
N
N H
HN
X
Nu + X
R
Ms
N
N
N H
+ R
NH2 Ms
H 3O
NH2 N
N
H 2N
NH2
N N
Ms
NH2
H 2N
Ms
Nucleophilic Aromatic Substitution Reaction
F
a
X
EW
Nu EW
HN
NH
O 2N
NH2
HN Sn, HCl
NO2
NH2 NH2 H2N
BuHN
b
N BuHN
N N
NH2
H 2N
BuHN N
Cl
BuHN
N
N N
NH
H 2N
NO2 O2N
Cl
BuHN
EW + X
Nu
X
NO2
O2 N
NH2
Nu
Cl
NH
N N
Cl
NH2
N BuHN
N N
NH NH N
BuHN N BuHN
N N
NH
N N
Cl
NH
∆
Diels-Alder Reaction
O
O O
Multiple Steps: Elaboration to Anthracene, Added Dendron
O
Scheme X. Dendrimers have been prepared using a variety of chemistries including SN2 (82), acylation chemistry (83, 84), the Wittig reaction (85), Friedel–Crafts chemistry (86), nucleophilic substitution (39, 87), and the Diels–Alder reactions (88).
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Acknowledgments The authors thank Robert A. Welch Foundation for support (A-1439). Sergio O. Gonzalez is supported by a predoctoral fellowship from the Center from Integrated Microchemical Systems (TAMU). Literature Cited 1. Newkome, G. R.; He, E.; Moorefield, C. N. Chem. Rev. 1999, 99, 1689–1746. 2. Bosman, A. W.; Janssen, H. M.; Meijer, E. W. Chem. Rev. 1999, 99, 1665–1688. 3. Vogtle, F.; Fischer, M. Angew. Chem. Int. Ed. Engl. 1999, 38, 4000–4021. 4. Frechet, J. M. J. Science 1994, 263, 1710. 5. Moore, J. S.; Xu, Z. Macromolecules 1991, 24, 5893. 6. Newkome, G. R.; Gupta, V. K.; Baker, G. R.; Yao, Z. Q. J. Org. Chem. 1985, 50, 2003. 7. Francavilla, C.; Drake, M. D.; Bright, F. V.; Detty, M. R. J. Am. Chem. Soc. 2001, 123, 57. 8. Oosterom, G. E.; Reek, J. N. H.; Kamer, P. C. J.; Van Leeuwen, P. W. N. M. Angew. Chem., Int. Ed. 2001, 40, 1828. 9. Reetz, M. T.; Giebel, D. Angew. Chem., Int. Ed. 2000, 39, 2498. 10. (a) Niu, Y.; Yeung, L. K.; Crooks, R. M. J. Am. Chem. Soc. 2001, 123, 6840. (b) Chechik, V.; Crooks, R. M. J. Am. Chem. Soc. 2000, 122, 1243. (c) Zhao, M.; Crooks, R. M. Angew. Chem., Int. Ed. 1999, 38, 364. 11 (a) Arya, P.; Panda, G.; Rao, N. V.; Alper, H.; Bourque, S. C.; Manzer, L. E. J. Am. Chem. Soc. 2001, 123, 2889. (b) Bourque, S. C.; Alper, H.; Manzer, L. E.; Arya, P. J. Am. Chem. Soc. 2000, 122, 956. (c) Bourque, S. C.; Maltais, F.; Xiao, W.; Tardif, O.; Alper, H.; Arya, P.; Manzer, L. E. J. Am. Chem. Soc. 1999, 121, 3035. 12. Schlenk, C.; Kleij, A. W.; Frey, H.; Van Koten, G. Angew. Chem., Int. Ed. 2000, 39, 3445. 13. (a) Hovestad, N. J.; Eggeling, E. B.; Heidbuchel, H. J.; Jastrzebski, J. T. B. H.; Kragl, U.; Keim, W.; Vogt, D.; Van Koten, G. Angew. Chem., Int. Ed. 1999, 38, 1655. (b) Kleij, A. W.; Gossage, R. A.; Gebbink, R. J. M. K.; Brinkmann, N.; Reijerse, E. J.; Kragl, U.; Lutz, M.; Spek, A. L.; Van Koten, G. J. Am. Chem. Soc. 2000, 122, 12112. 14. Mager, M.; Becke, S.; Windisch, H.; Denninger, U. Angew. Chem., Int. Ed. 2001, 40, 1898. 15. De Groot, D.; De Waal, B. F. M.; Reek, J. N. H.; Schenning, A. P. H. J.; Kamer, P. C. J.; Meijer, E. W.; Van Leeuwen, P. W. N. M. J. Am. Chem. Soc. 2001, 123, 8453. 16. Sellner, H.; Seebach, D. Angew. Chem., Int. Ed. 1999, 38, 1918. 17. Koellner, C.; Pugin, B.; Togni, A. J. Am. Chem. Soc. 1998, 120, 10274. 18. Breinbauer, R.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2000, 39, 3604. 19. Schmitzer, A. R.; Franceschi, S.; Perez, E.; Rico-Lattes, I.; Lattes, A.; Thion, L.; Erard, M.; Vidal, C. J. Am. Chem. Soc. 2001, 123, 5956. 20. (a) Hofkens, J.; Maus, M.; Gensch, T.; Vosch, T.; Cotlet, M.; Koehn, F.; Herrmann, A.; Muellen, K.; De Schryver, F. J. Am. Chem. Soc. 2000, 122, 9278. (b) Tsuda, K.; Dol, G. C.; Gensch, T.; Hofkens, J.; Latterini, L.; Weener, J. W.; Meijer, E. W.; De Schryver, F. C. J. Am. Chem. Soc. 2000, 122, 3445.
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21.
22. 23. 24. 25. 26.
27. 28.
29.
30.
31. 32.
33.
34. 35. 36. 37. 38. 39. 40. 41.
42. 43.
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