Functional bead shaped materials used in combinatorial chemistry.

1. FUNCTIONAL BEAD SHAPE
MATERIALS
SYNTHESIS AND
CHARACTERIZATION
HIRA AROOJ

2. 1
COMBINATORIAL
CHEMISTRY
2
FUNCTIONAL
MATERIALS
3
TYPES OF
FUNCTIONAL
MATERIALS
4
SOLID
SUPPORTS
5
LINKERS
`AGENDA

3. COMBINATORIAL
CHEMISTRY
The generation of large
collections, or ‘libraries’,
of
compounds by synthesizing
all
possible combinations of a
set of
smaller chemical
structures, or
‘building blocks’.

4. FUNCTIONAL
MATERIALS
Can be used for
two purposes
Solid supports
Linkers
4
Either provide attachment or site for
synthesis, contains functional groups.

5. Solid Supports
5
 Must be insoluble in solvent
 Do not react chemically with reagents
 reactions take place both inside and at the surface of the
solid particles
 mostly used in the form of small resin beads that swell in
the solvents applied in the synthesis
 The reactions in other kinds of supports take place only
at the surface. These supports are used as polymer or
glass beads, rods, sheets etc. and (except their surface
layer) do not swell in the solvents.
 The solid supports are usually composed of two parts:
the core and the linker. The starting compound of the
synthesis is attached to the support via the linker.
core Linker
Start
compound
ensures the
insolubility of the
support,
determines the
swelling
properties,
provides
functional group
determines the
reaction
conditions for the
cleavage

6. TYPES OF
SOLID
SUPPORTS
Cross linked
POLYSTYRENE Resin
PEG grafted
polymer
Cellulose beads
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1 2 3

7. POLYSTYRENE RESIN
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 The ratio of divinylbenzene to styrene
determines the density of cross links.
 Higher crosslink density increases the
mechanical stability of the beads.
 Lowering the crosslink density, on the other
hand, increases swelling and increases the
accessibility of the functional groups buried
inside the beads.
 In practice, mostly 1-2% divinylbenzene is used.
 Hydrophobic swells only in apolar solvents.
 Functional groups can be introduced into the
resin by two approaches: either by post
functionalization of the aromatic rings of
polystyrene, or by using functionalized styrene in
polymerization.

8. 1.POLYSTYRENE
RESIN
8
Preparation, characterization and
functionalization of EGDMA–PS support
Styrene Etylene Glycoldimethacrylate
Bz202
80 C

9. 9
CHARACTERIZATIONBYNMR
The 13C CPMAS NMR spectrum
exhibited an intense peak at 130×6
ppm corresponding to the aromatic
carbon of the styrene and a small
peak at 148×1 ppm arising from the
C3 carbon of styrene. The methylene
carbons of the polymer backbone
gave a singlet at 42×7 ppm.

10. 10
CHARACTERIZATIONBYIR
The IR spectrum of PS–EGDMA resin
showed a sharp band 1720 cm–1
corresponding to the ester carbonyl
group of the cross-linking agent

11. 11
FUNCTIONALIZATION
The cross-linked polymer with 200–
400 mesh size was functionalized via
Friedel– Crafts chloromethylation
reaction using chloromethyl methyl
ether in presence of anhydrous ZnCl2
as catalyst at 50°C . The IR spectrum
of the chloromethylated resin
showed characteristic C–Cl stretching
at 680 cm–1.

12. 2.POLYETHYLENE
GLYCOL(PEG)
GRAFTEDSUPPORTS
12
PEG-grafted polystyrene has a 1-2%
crosslinked polystyrene core and to its
aromatic rings, polyethylene glycol chains
are covalently attached. Its commercial
name is Tentagel.
The advantage of the PEG-grafted
polystyrene is that the substrate at the end
of a flexible chain is more accessible to
reagents. It behaves like being in a
solution-like environment. The PEG-chains
gives a hydrophilic character to the resin
and swells well in water and methanol but
poorly in ether or ethanol.

13. CELLULOSE BEADS
13

14. The preparation of spherical cellulose beads was described for
the first time in 1951. The materials, then named cellulose
pellets, were simply prepared by hand-dropping a viscose
solution into an aqueous coagulation bath. Since that report,
various procedures for obtaining cellulose beads with
diameters ranging from about 10 μm to 1−3 mm have been
developed using different solvents and techniques to obtain
spherical particles. In principle, bead production can be
simplified into three steps: (i) dissolution of cellulose (or a
cellulose derivative), (ii) shaping of the polysaccharide
solution into spherical particles, and (iii) sol−gel transition and
solidification of the solution particles to beads.
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PREPARATION
OFCELLULOSE
BEADS

15. 1. SHAPING INTO SPHERICAL PARTICLES
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16. DISSOLUTION AND REGENERATION OF CELLULOSE
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17. PROPERTY TUNNING
By the chemical modification of cellulose beads, it is possible to tune chemical and adsorption properties in
particular . A possibility for modifying physical properties is to include inorganic substances in cellulose
beads. The compounds are directly added to the cellulose (or cellulose derivative) solution prior to the
shaping process. Upon regeneration of the polysaccharide, the particles are trapped within the beads due to
their large size, relative to the mean pore diameter.
If entrapped macroscopic particles are removed from the cellulose beads, void cavities are generated that
result in highly porous materials. Cellulose beads with macroscopic pores have been prepared by the
inclusion of inorganic salts with defined particle sizes, for example, Na2SO4 or CaCO3, and subsequent
removal by washing with aqueous solution. In a comparable approach, starch has been incorporated into
cellulose beads and was finally removed again by amylase treatment generating a porous material. In
addition, enzymatic hydrolysis of pure cellulose beads with cellulase has been carried out to increase the
pore diameter. However, it is reasonable to assume that enzymatic degradation of cellulose starts at the
edge of the beads and only slowly progresses into the interior. An uneven pore size distribution along the
lateral cross section should be the result. Another possibility for producing highly porous cellulose beads is
to add “blowing agents”, such as NaHCO3 or azodicarbonamide to the cellulose solutions. During the
coagulation process, these compounds decompose under the liberation of inert gases, which results in the
formation of macroscopic pores.

18. Morphology Biocompatibility
Size and shape
Via image analysis
through microscope
By Scanning Electron
Microscope
In-vivo in-vitro
analysis
CHARACTERIZATION

19. Inorganic supports
• Glass beads with controlled pore size can be
manufactured and are commercially
available. The glass beads can be
functionalized and can be used as supports in
solid phase synthesis. The mechanical
stability of such glass beads surpass that of
the resin beads but do not swell in solvents.
Functionalized ceramics can also be used as
supports.
Non-bead form supports
• Polymers can be used as supports for solid phase
synthesis not only as microscopic beads but also in the
form of macroscopic objects if their surface can be
functionalized with groups that can serve as anchors to
hold the substrate in a reasonable quantity. Using
appropriate monomers like styrene or others,
polyolefin chains can be grafted by radiation into the
surface of the objects and the chains can be
functionalized.
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20. LINKERS,ANCHORS
The initial building block of the compound to
be prepared by solid phase synthesis is
covalently attached to the solid support via
the linker. The linker is a bifunctional
molecule. It has one functional group for
irreversible attachment to the core resin and
a second functional group for forming a
reversible covalent bond with the initial
building block of the product. The linker that
is bound to the resin is called anchor.
The anchor can also be considered as a
protecting group of one of the functional
groups of the final product and, as such, it
determines the reaction conditions by which
the product can be cleaved from the support.
A large variety of the commercially available
resins contain the already built in anchor.
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21. Linkers
Merrifield
resin
Hydroxymethyl
resin.
Photolabile
anchors.
Trityl chloride
resin. Wang resin.
Rink amide
resin.
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22. Merrifieldresin
Attachment
Carboxylic acids
Preparation
by chloromethylation of
polystyrene or by the
copolymerization
of styrene and 4-vinylbenzyl
chloride
Cleavage
HF
Characterization
Spectroscopic
techniques
22

23. Attachment
carboxylic acids,
alcohols,
phenols, amines
Application
Peptide synthesis
Cleavage
TFA (2-50%)
Characterization
Spectroscopic
techniques
23
Tritylchloride
resin.

24. Attachment
activated
carboxylic acids
Preparation
from Merrifield resin by stirring in DMA
with slight excess of PA to form
acetoxymethyl resin , which on reduction
with LiAlH4 or hydrazinolysis yielded the
desired hydroxymethyl resin
Cleavage
HF
Characterization
Spectroscopic
techniques
24
Hydroxymethyl
resin.

25. Attachment
Carboxylic acids
Application
Peptide synthesis
Cleavage
95%TFA
Characterization
Spectroscopic
techniques
25
Wangresin.

26. Attachment
amino acid at the
C-terminus as an
ester
Example
2-nitrobenzhydrylamine
resin below, usually
contain nitro group that
absorbs UV light.
Cleavage
Irradiation
Characterization
Spectroscopic
techniques
26
Photolabile
anchors

27. Attachment
Carboxylic acids
Preparation
swelling an Fmoc-amide monomer
with double bonds, styrene and
divinyl benzene by adopting
polystyrene microspheres seeds;
and with benzoyl peroxide as an
initiator, polyvinyl alcohol as a
stabilizing agent and lauryl sodium
sulfate as an emulsifier, preparing
Rink amide resin microspheres.
Cleavage
in carboxamide
form can be performed with
dilute (~1%) TFA
Characterization
27
Rinkamideresin
Spectroscopic
techniques

28. THANKYOU
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