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Arjan W. Kleij et al- Polycationic (Mixed) Core ± Shell Dendrimers for Binding and Delivery of Inorganic/Organic Substrates

Arjan W. Kleij et al- Polycationic (Mixed) Core ± Shell Dendrimers for Binding and Delivery of Inorganic/Organic Substrates

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Polycationic (Mixed) Core±Shell Dendrimers for Binding andDelivery of Inorganic/Organic Substrates
Arjan W. Kleij,
[a]
Rob van de Coevering,
[a]
Robertus J. M. Klein Gebbink,
[a]
Anne-Marie Noordman,
[a]
Anthony L. Spek,
[b]
and Gerard van Koten*
[a]
Abstract:
The convergent synthesis of aseries of polycationic aryl ether den-drimers has been accomplished by aconvenient procedure involving quanti-tative quaternarization of aryl(poly)-amine core molecules. The series hasbeen expanded to the preparation of thefirst polycationic, mixed core±shell den-drimer. All these dendrimers consist of an apolar core with a peripheral ioniclayer which is surrounded by a less polarlayer of dendritic wedges. These cation-ic, macromolecular species have beeninvestigated for their ability to formassemblies with (anionic) guest mole-cules. The results obtained from UV/Visand NMR spectroscopies, and MALDI-TOF-MS demonstrate that all the cat-ionic sites throughout the dendrimercore are involved in ion pair formationwith anionic guests giving predefinedguest/host ratios up to 24. The largeNMR spectroscopic shifts of resonancescorrelated with the groupings located inthe core of the dendrimers, togetherwith the relaxation time data indicatethat the anionic guests are associatedwith the cationic core of these dendrim-ers. The X-ray molecular structure of theoctacationic, tetra-arylsilane model de-rivative [Si(C
6
H
3
{CH
2
NMe
3
}
2
-3,5)
4
]
8
´
8I
À
shows that the iodide counterionsare primarily located near the polycat-ionic sphere. The new polycationic den-drimers have been investigated for theircatalytic phase-transfer behavior andsubstrate delivery over a nanofiltrationmembrane.
Keywords:
dendrimers
´
nanofiltra-tion
´
noncovalent interactions
´
phase-transfer catalysis
´
polyca-tions
Introduction
Dendritic polymers
[1]
with regular and well-defined uni-molecular architectures currently attract much interest assoluble supports
[2]
or as so-called dendritic boxes or molecularcontainers.
[3]
The micro-environment inside these materials isusually less densely packed compared with the stericallycongested outer shell, which enables the encapsulation of (small) organic guests in the dendritic host. The latter offersthe possibility to convert these macromolecules into bio-logically important delivery systems which can release organicguest molecules by means of external stimulus, for exampleirradiation or pH changes.
[4]
Most of the dendritic containersreported so far use the concept of closing the dendrimersurface in order to be able to keep the guest molecules insidethe dendrimer host. In this case, high generation dendrimerspecies with sufficient loading of peripheral groups areneeded for an effective binding of guest molecules insidetheir cavities. However, up to now, few reports exist on well-defined molecular containers that exhibit flexible bindingproperties specifically inside its internal cavities which do notdepend on the peripheral crowding of the system but solely onthe binding properties at the core.
[5a±c]
Here, we focus on this particular aspect by using a differentapproach of binding guest molecules inside dendritic hostsystems. Two types of polycationic species
[5d]
were designed;the first one is constructed from polyaryl(di)amine coremolecules and contains an ionic core shell and a less polarouter shell. The second type is derived from a relatively large,carbosilane dendritic core producing polycationic mixedcore±shell dendrimer species with a potentially variable,but with a distinct distance between the core of the moleculeand the ionic layer (Figure 1).These new polycationic dendrimers can potentially be usedfor the multiple incorporation of anionic guests inside theircore or cavities. Both types of cationic dendrimers should becapable of specific binding to a number of different anionic,
[a] Prof. Dr. G. van Koten, A. W. Kleij, R. van de CoeveringDr. R. J. M. Klein Gebbink, A.-M. NoordmanDebye Institute, Department of Metal-Mediated SynthesisUtrecht University, Padualaan 8, 3584 CH Utrecht (Netherlands)Fax: (
31)30-2523615E-mail: g.vankoten@chem.uu.nl[b] Prof. Dr. A. L. SpekBijvoet Center for Biomolecular ResearchDepartment of Crystal and Structural ChemistryUtrecht University, Padualaan 8, 3584 CH Utrecht (Netherlands)E-mail: a.l.spek@chem.uu.nlSupporting information for this article is available on the WWW underhttp://www.wiley-vch.de/home/chemistry/ or from the author.
FULL PAPER
Chem. Eur. J.
2001
,
, No. 1 WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001 0947-6539/01/0701-0181 $ 17.50+.50/0
181
 
FULL PAPER
G. van Koten et al.
 WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001 0947-6539/01/0701-0182 $ 17.50+.50/0
Chem. Eur. J.
2001
,
, No. 1
182
organic substrates through electrostatic forces
[6]
regardless of the steric features on the surface. Moreover, this behavior islikely to be fully reversible, which could be relevant for aneventual reuse of the system. The application of these systemsin phase-transfer catalysis and substrate delivery over ananofiltration membrane is presented.
Results and Discussion
Synthesis of model species
: In order to investigate whetherarylamine building blocks could be used for the constructionof larger (dendritic) macromolecules, we first carried outquaternarization of a model tetra-arylsilane compound,namely Si(C
6
H
3
{CH
2
NMe
2
}
2
-3,5)
4
(abbreviated as Si(NCN)
4
)(
1a
)
[7]
with various alkyl halides. In order to be able to varythe amount of anchoring groups and the final structure of thepolycationic products we have also prepared core molecule
1b
(Scheme 1). Core molecules
1a
and
1b
give rise to eightand four ammonium centers, respectively, after quaternariza-tion. Core molecule
1b
was obtained as a white solid by in situtreatment of an excess of [LiC
6
H
4
(CH
2
NMe
2
)-4] with SiCl
4
inEt
2
O at
À
78
8
C as described earlier for
1a
.
[7]
Treatment of 
1a
with an excess of methyl iodide at RT inCH
2
Cl
2
led to the immediate precipitation of a white solidmaterial, which was isolated by centrifugation.
1
H NMRspectroscopic analysis performed in D
2
O pointed to selectiveformation of the octatrimethylammonium derivative[Si(C
6
H
3
{CH
2
NMe
3
}
2
-3,5)
4
]
8
´
8I
À
(
2
) in nearly quantitative
Figure 1. Schematic representation of two types of polycationic macro-molecular hosts for anionic guest molecules.
BrNRMe
2
NRMe
2
SiMe
2
RNNRMe
2
Me
2
RNMe
2
RNNRMe
2
Me
2
RNSiNMe
2
NMe
2
2. SiCl
4
SiNMe
2
NMe
2
BrNMe
2
NMe
2
2. SiCl
4
4++++++++X
 
 – 
X
 
 – 
X
 
 – 
X
 
 – 
X
 
 – 
X
 
 – 
X
 
 – 
X
 
 – 
2
R = Me, X = I
3
R = Et, X = Br
4
R = Oct, X = I
1b1a
Et
2
O, -78
0
o
C1. 2 equiv
BuLi4excess RXCH
2
Cl
2
, RTEt
2
O, -78
0
o
C1. 2 equiv
BuLi
core molecules
Scheme 1. Synthesis of core molecules
1a
and
b
and model polycationicspecies
2
±
4
.
Abstract in Dutch:
Dit onderzoek beschrijft een serie poly-kationische arylether-dendrimeren, die in kwantitatieve op-brengst zijn verkregen door reactie van dendritische benzybromides met organosilanen die vier aryl(di)amine substituen-ten bevatten. Deze dendrimeren zijn opgebouwd uit een polykationische kern en een polaire buitenlaag. Tevens wordt de synthese van het eerste gemengde, polykationische dendri-meer beschreven. Dit nieuwe type dendrimeer bestaat achter-eenvolgens uit een [G1] carbosilaandendrimeer kern, een poly-ionische tussenlaag en een polaire buitenlaag opgebouwd uit [G1] Fre chet type dendrons. De bindingscapaciteiten van dezedendrimeren ten aanzien van anionische gast-molekulen zijnonderzocht. Spectroscopische metingen (UV/Vis, NMR enMALDI-TOF) wijzen erop dat alle kationische centra in dedendrimeren beschikbaar zijn voor de vorming van ionparen.Zo is het mogelijk om een maximum aantal van 24 anionische gasten te binden. De grote NMR spectroscopische verschuivin- gen gecombineerd met relaxatiemetingen van de groepen dieaanwezig zijn in de kern van de dendrimeren, duiden op eenduidelijke associatie van de anionen met de kationische centravan de dendrimeren. De kristalstructuur van de octakationi- sche model-verbinding [Si(C 
6
 3
{CH 
 2
NMe
 3
 }
 2
-3,5)
4
 ]
8
´
8
À
laat zien dat de (jodide) anionen zich voornamelijk in de buurt vande kationische centra bevinden. De nieuwe polykationischedendrimeren zijn gebruikt in fase-transfer katalyse en voor het transport van organische substraten door nanofiltratiemem-branen.
 
Polycationic Dendrimers 181±192
Chem. Eur. J.
2001
,
, No. 1 WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001 0947-6539/01/0701-0183 $ 17.50+.50/0
183
yield. This procedure provedto beof general use and the octa-ethyl and octa-octyl derivatives
3
and
4
were also isolated aswhite solids in good yields by treatment of 
1a
with ethylbromide and octyl iodide, respectively (Scheme 1).Compounds
2
±
4
are hygroscopic solids melting between73±77
8
C without decomposition, unlike the polycationicmaterials prepared by Stoddart et al.
[8]
The composition of 
2
±
4
was confirmed by NMR spectroscopy, fast atom bombard-ment (FAB) mass spectroscopy, and elemental microanalysis.The FAB mass spectra of 
2
±
4
showed characteristic isotopicdistributions at
m
/
z
1801.0, 1585.1, and 2587.0, correspondingto [
2
À
I]
, [
3
À
Br]
, and [
4
H
À
I]
, respectively. Besidethese easily assignable peaks, the spectra also showed othercomplicated isotope patterns that most likely resulted fromthe exchange of halide anions with matrix molecules,
[9a]
aswell as degradation of the quaternary ammonium salts viaC
À
N bond cleavage.
[10]
The solubility characteristicsof these dendritic cationic de-rivatives varied upon increasingthe length of the alkyl halide:Octamethylated
2
is only solu-ble in H
2
O and MeOH whereasthe octa-octylated derivative
4
is insoluble in water and dis-solves readily in relatively non-polar solvents such as CH
2
Cl
2
and CHCl
3
. This effect can berationalized by assuming thatthe aliphatic octyl chains in
4
strongly interact with each oth-er and thus shield the hydro-philic polycationic core, similarto a reversed micelle. The
1
H NMR spectra recorded for
4
at different concentrationsshowed more than one set of resonances for the aromaticprotons and CH
2
N and NMe
2
groupings. Similar dependen-cies of the NMR spectroscopicpatterns on the concentrationof dendritic ammonium saltshave been reported.
[9b]
X-ray crystal structure of 2
:Although several groups havecharacterized organic mole-cules crystallographically con-taining triorganoammonium io-dide moieties,
[11]
the structureof 
2
in the solid state is the firstexample of a polyammoniumderivative containing morethan four of such groupingswithin a single molecule. More-over, this X-ray crystal struc-ture can be regarded as a rep-resentative model for the poly-cationic core of the dendrimer species presented here (seebelow). Crystals of 
2
were obtained from a 2:1 mixture of MeOH/EtOH at
À
20
8
C. The polycationic part of themolecular structure of 
2
is depicted in Figure 2, top andrelevant bond lengths and angles are given in Table 1.Crystallographic data and other related details are summar-ized in the Experimental Section.It should be noted that the refinement of the data wastroublesome because of the large disorder of the solventmolecules and partial disorder of the iodide anions. A firstimpression of the unique solid state structure of octacationic
2
could be obtained emphasizing a fully methylated species witheight quaternarized amine moieties forming a soft, cationicsphere at about 5.9  from the centroid Si center. Althoughpartially disordered, the larger part of the iodide anions areprimarily located near/between the cationic centers (Figure 2,
Figure 2. Top: Displacement elipsoid plot (ORTEP, 50% probability level) of the polycationic part of themolecular structure of 
2
. Hydrogen atoms, iodide anions, and cocrystallized, disordered solvent molecules havebeen omitted for clarity. Bottom: Space-filling model of the molecular structure of the polycationic unit of 
2
together with the iodide anions.

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