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Highlights from 50 Years Biosynthetic
Supramolecular Chemistry Hans-Jörg Schneider FR
Organische Chemie der Universität des Saarlandes
, D 66041 Saarbrücken/ Germany This is a
presentation for/from only one hour- so many
important contributions had to be neglected this
version has short questions marked Q1 etc on most
pages- possible answers are at the end

Outline Some History Artificial
Enzymes Affinity and Selectivity of
supramolecular complexes Complexation of
Peptides Nucleotides /Nucleosides Interference
with Biopolymers DNA/RNA e.g.a artificial
helicase protein drug interactions
protein-protein interactions Nanoparticles
binding biomolecules Molecular Recognition with
Microarrays / Chips Artificial photosynthetic
systems / Light energy conversion Supramolecular
chemistry with polymers -Artificial Muscles
2
Some History Emil Fischer. Lock and Key as
Enzyme Model 1894 Inclusion Compounds Paul
Pfeiffer Organische Molekülverbindungen
1927 1950- 1975 mostly principles of enzyme
mechanisms / models Koshland induced
fit Proc Natl Acad Sci U S A. 1958
Covalent enzyme models e.g. Bruice BBA 1958, 208
Proc. Nat. Acad. Sci. USA 1960 W.P. Jencks,
Catalysis in Chemistry and Enzymology,
1989 A.J. Kirby Enzyme Mechanisms, Models, and
Mimics Angew. Chem. Int. Ed. Engl. 2003 Warshel
et al Chem. Rev. 2006, 3210 (electrostatic
origin.... ) Q1a why in these years so few
practical applications ? The begin of
supramolecular enzyme models by Friedrich
Cramer Q1b why are Cramers papers often
forgotten ? Einschlussverbindungen Review
Angew. Chem. 1952, 437 ( ... es ist uns
vor kurzem tatsächlich gelungen, Reaktionen zu
finden, die durch Einschlußverbindungen
katalysiert werden....) Enzym-Modelle Angew.
Chem. Int. Ed. Engl. 1962, 434 Tetr. Lett.
1962, 353 Catalysis of Decarboxylation by
Cyclodextrins - a Model Reaction for Mechanism of
Enzymes. J. Am. Chem. Soc. 1965,
1115 Catalysis of Fission of Pyrophosphates by
Cyclodextrin J. Am. Chem. Soc. 1965, 1121
Hans-Jörg Schneider Highlights from 50 Years
Biosynthetic Supramolecular Chemistry
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Artificial Enzymes ML Bender, M Komiyama
Cyclodextrin Chemistry, Reactivity and Structure
1978 (e.g. FM Menger, ML Bender J. Am. Chem.
Soc.1966, 131 ) VT D'Souza, ML Bender - Acc.
Chem. Res. 1987, 146 R. Breslow , Chem. Rev.
1998,1997 Acc. Chem. Res. 1980, 170 R. Breslow,
(Ed.) Artificial Enzymes, 2005 Murakami et al.
Chem. Rev. 1996, 721
R Breslow, P Campbell - J. Am. Chem. Soc. 1969
,3805 Regioselectivity change o-anisol inside
a -CD Q2b other possible hosts ? HOCl
substitution ratio changes from po 1.5 to
22 with a -CD                          
Hans-Jörg Schneider Highlights from 50 Years
Biosynthetic Supramolecular Chemistry
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For most chemical reactions there are no enzymes
Q3a alternatives ? but supramolecular
catalysts
Change of Regioselectivity Q3a why? and of
Speed Q3b why? Schneider, Busch Ang Chem 1984
CP66
Neat 2 1 CP66 6.3 1 Me4NCl
0.15 1 Me4NCl has opposite
effect 40-fold change of regioselectivity Hans-
Jörg Schneider Highlights from 50 Years
Biosynthetic Supramolecular Chemistry
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e.g. Catalysis of Diels-Alder Reactions by
Cyclodextrins (CD)  Breslow et al 1980
f Schneider et al 1986
a) Diastereoselectivity increase Q4a why ?
without CD 48 1 with CD
112 1  
Rate increase max. 70 Q4b limitation why
? with ethylfumarate EF inhibition
b) Chiral induction 21 Q4c how to improve ?

Hans-Jörg Schneider Highlights from 50 Years
Biosynthetic Supramolecular Chemistry
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Non-covalent interactions as basis ADH /NADH
mimics
 
Vekemans, Buck (1989) gt 95 ee Q5 why ? Kellog
( 1985) gt90 ee supramolecular complexes
perform not always better Other NADH analogs
( see e.g. Murakami Chem. Rev 1996, 721 Behr
and Lehn / Skog and Wennerström / Toda /
Engbersen / Murakami / Inoue /Bourguignon /
Davies / Gelbard / Iwata / Meyers .
Hans-Jörg Schneider Highlights from 50 Years
Biosynthetic Supramolecular Chemistry
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Synthetic Hydrolases Breslow, R. Zhang, B. J.
Am. Chem. Soc. 1994, 116, 7893, (Related
hydrolases with cyclophanes Tabushi, Murakami,
Lehn, Diederich.) 220 000-times faster than
uncatalyzed / at least 50 turnovers Q6a what is
the drawback ?
binding group reaction site substrate
Artificial RNAses Breslow etc Q6b why is RNA
hydrol faster than of DNA ?
Hans-Jörg Schneider Highlights from 50 Years
Biosynthetic Supramolecular Chemistry
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Artificial Nucleases E. Kimura J. Chin J.
N. Burstyn R. Krämer J. Engbersen/ D. N.
Reinhoudt, R. Franklin M. Komiyama, J. R.
Morrow, H. Lönnberg JM Lehn HJ Schneider,
A.Yatsimirski , T. Bruice, W. Göbel, A. Hamilton

BNPP as model for DNA , Parathion , Soman, VX
etc hydrolysis M Eu(III) BNPP ko 2.5 x
10-8 s-1 at 75C t ½ ? 100.000
hrs kcat/kuncat 107 (Schneider et al TL
2002 ) Q7a any practical applications ? Q7b role
of metalion ? of naphthyl units ? Q7c
adanvantage of Ln instead of e.g. Zn
ions? kcat/kuncat 107 Hegetschweiler et
al, Inorg. Chem., 2001,4918 Q7d role of metalion
?
Hans-Jörg Schneider Highlights from 50 Years
Biosynthetic Supramolecular Chemistry
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(1) Serin protease analogs CH2OH pKa 7.4 Q8a
role of metalion ? Kimura et al
(2) with dinuclear Eu(III)cplx kdinucl /
kmononucl 70 (BNPP) plasmid DNA 80
hydrolysis Q8b why 2 ions? Schneider et al
Angew.Chem 1996, 1219
(3) with simple cofactors 6 fold increase
(Eu(III) plasmid DNA Q8c how does it work
? Schneider et al Eur. J. Org. Chem, 2001. 205
Alkaline Phosphatase Q8d identify role of the
diffent amínoacids E.E.Kim H.W.Wyckhoff
J.Mol.Biol. (1991) 449
Hans-Jörg Schneider Highlights from 50 Years
Biosynthetic Supramolecular Chemistry
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Artificial Restriction Enzymes M. Komiyama J.
Biochem. 1995, 665 Q9a the basis of the
selectivity ? Q9b analytical method ? Q9c
adanvantage of Ce instead of e.g. Zn ions?
scission
Hans-Jörg Schneider Highlights from 50
Years Biosynthetic Supramolecular Chemistry
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Cytochrome P-450 models
C-6 hydroxylation , up to 3000 turnovers ,
with M Mn, and PhIO Breslow et al J. Org.
Chem. 2002, 67,5057 Q10a drawback of the
substrate ? Q10b which metal ions work ? Others
Nolte et al. P-450 vesicles
Diederich et al. porphyrin-bridged cyclophanes
Alkene epoxidation Q10c why so many F ? Ogoshi
et al J. Am. Chem. Soc. 1989, 1912
Hans-Jörg Schneider Highlights from 50 Years
Biosynthetic Supramolecular Chemistry
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Vitamin B1 Thiamine pyrophosphate TPP analogs
2-naphthaldehyde oxidation kcat/KM,
75 1 also useful for benzoin condensation etc
Diederich, et al Angew. Chem. 1986, 1125.
Vitamin B12-functions radical rearrangements
(methylmalonyl-CoA mutase) methylation
(methionine synthetase)
Murakami et al. Chem. Rev. 1996, 721
Hans-Jörg Schneider Highlights from 50 Years
Biosynthetic Supramolecular Chemistry
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glycine acetaldehyde gt threonine / up to 75
ee Breslow et al J. Am. Chem. Soc. 1994,
11234. Artificial Aldolases etc
Others transaminations (ß-keto acid gt
aminoacid , (vitamin B6- dependent
aminotransferase) ( eg Kuzuhara, Murakami,
Breslow et al ) e-transfer Vitamin B2
Functions / Flavoenzymes ( e.g Tabushi,
DeSouza, Diederich...)
Hans-Jörg Schneider Highlights from 50 Years
Biosynthetic Supramolecular Chemistry
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Affinity of Synthetic Receptors beating
Biotin-Avidin  (K 1017 M-1) Q13a practical
use of Biotin-Avidin interaction ?
Rekharsky, Kaifer, Isaacs, Gilson, Inoue et
al Proc. Natl. Acad. Sci. USA 2007,
20737 Q13c why is small TDS so unusual
? Whitesides et al Science 1998, 708 Complexes
tripeptide with K 1017 M-1 Q13b why so high
affinity ?
Hans-Jörg Schneider Highlights from 50 Years
Biosynthetic Supramolecular Chemistry
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Selectivity of Synthetic Receptors
Calixarene-crown ethers best complex K/ Na
selectivity beats valinomycin (X
CH2CH2(OCH2CH2)n, n 3 or 4, R alkyl)
(Ungaro, Reinhoudt et al , 1990
Selectivity-Affinity Correlations Q14a theor.
reason for Selectivity-Affinity Correlation
? Schneider, Yatsimirsky Chem.Soc.Rev. 2008, 263

18crown6 complexes less linear correlation of D
lgK (K/Na) vs. lgK(K) Q14b why more scatter
? Q14c why less selective than calix-crown ?
Hans-Jörg Schneider Highlights from 50 Years
Biosynthetic Supramolecular Chemistry
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Supramolecular receptors für biologically
important targets e.g. Peptides
König et al J. Am. Chem. Soc., 2005, 3362
s.also König Chem. Rev. 2006, 106, 3520 Q15a
Role of Cu? Why Cu ?
e.g. Gly-Gly-Phe lg K 4.4 Schneider et al
Chem. Comm.. 1999, 907 Q15b which interaction
mechanisms ?
Hans-Jörg Schneider Highlights from 50 Years
Biosynthetic Supramolecular Chemistry
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Peptide recognition / length and sequencence
selective
Ternary complex with MV and peptide within
cucurbit8uril Q16a which detection method
? Q16b other host ? E. Meghan N.D. Bouley, A.
R. Urbach, J. Am. Chem. Soc., 2005, 127, 14511
Linear adjustable host with crown for
peptide-NH3- hydrogen
bond NMe3- for peptide-COO-
ion pair Lipoph group L for side chain
group R stacking Q16c why fluorescence emmision
upon complexation? Q16d which interaction
mechanisms ? (see next transparancy) Q16e
performance in other solvents than water
? Hossain, Schneider J. Am. Chem. Soc., 1998,
11208
Hans-Jörg Schneider Highlights from 50 Years
Biosynthetic Supramolecular Chemistry
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Phe
-NH3
Stacking
Ion pairing
-COO-
Dansyl selector group
Crown ether
Hydrogen bonding
Hans-Jörg Schneider Highlights from 50 Years
Biosynthetic Supramolecular Chemistry
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Hans-Jörg Schneider Highlights from 50 Years
Biosynthetic Supramolecular Chemistry
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Receptors for Nucleotides / Nucleosides
 K from 5.000 M-1 to 430.000 M-1 Small charge
effects Adenosin lgK 4.8, ATP lgK 4.5
only small nucleobase selectivity Q19a which
mechanism dominates ? Q19b which measuring method
?
M. Sirish, H. J. Schneider, Žinic, Vigneron,
Lehn, J. Am. Chem. Soc. 2000, 122, 5881
Chem. Commun. 1995, 1073
Stacking but controlled by charge Malojcic,
Piantanida, et al.OBC 2005,4373
With metal complexes Yajima, Maccarrone, et al.
Chem. Eur. J. 2003 ,3341
with amino-cyclodextrins e.g. ATP K 106
M-1 Schneider et al , J. Am. Chem. Soc. 1994,
6081 Darcy et al, Perkin Trans 2, 1998 , 805
Menuel, Duval, et al. New J. Chem, 2007, 995
(guanidinium deriv.)
Aminocyclodextrins for gene delivery /as
vector E. Redenti et al Adv. Drug Deliv. Rev..
2001, 235 f Alzheimer amyloid cplx J. X. Yu,
et al J. Mol. Neuroscience 2002, 51
Hans-Jörg Schneider Highlights from 50 Years
Biosynthetic Supramolecular Chemistry
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Interference with Biopolymers High affinity and
selectivity in DNA/ RNA groove binding
pyrrole-imidazole hairpins binds to ds-DNA with
subnanomolar affinity Alkylation of A, mostly in
pure A/T tracts, by the electrophilic
cyclopropyl residues Q21 what is the binding
mechanism ? Why so high affinity ? P.B. Dervan,
et al Top. Curr. Chem. 2005 , 1-31
Hans-Jörg Schneider Highlights from 50 Years
Biosynthetic Supramolecular Chemistry
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DNA/ RNA Groove binding, e.g. antibiotics
Q22a what binding interaction ? Q22b origin of
difference between DNA and RNA ?
Hans-Jörg Schneider Highlights from 50 Years
Biosynthetic Supramolecular Chemistry
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Interference with Biopolymers
Artificial Helicase Destabilization of
double-stranded nucleic acids stabilize
unfolded parts of DNA or RNA using a)
phenylderivatives will only intercalate into
unfolded parts b) few positive charges in the
ligands N stabilizes double-strands) Schnei
der et al Angew. Chem., Int. Ed. 1998, 37, 3016

Hans-Jörg Schneider Highlights from 50 Years
Biosynthetic Supramolecular Chemistry
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Interactions with Proteins Castellano, Diederich
Angew. Chem. Int. Ed. 2003, 1210 Zürcher,
Diederich J. Org. Chem. 2008, 73, 4345
anti-Alzheimer drug E2020 within active site of
acetylcholinesterase
tRNA-guanine transglycosylase (TGT) nucleobase
analogue Q24a identify all binding contributions
Alternating cationic (Arg, Lys) and aromatic
(Tyr, Phe, Trp) gt within human growth hormone
receptor (hGHR) Q24b identify all binding
contributions
Hans-Jörg Schneider Highlights from 50 Years
Biosynthetic Supramolecular Chemistry
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Interference with ProteinProtein Interactions
Review Hamilton et al Angew. Chem. Int. Ed.
2005, 4130 e.g. Calixarene derivative bound to
cytochrome-c / K 108 M-1 ion pairing

• a-chymotrypsin bound to nanoparticle receptor (
  ion pairing )
• V. M. Rotello et al Proc. Natl. Acad. Sci. USA
  2002, 5018.

Hans-Jörg Schneider Highlights from 50 Years
Biosynthetic Supramolecular Chemistry
26
Biomolecule-nanoparticle (NP) hybrids E. Katz ,
I. Willner, e.g.Angew. Chem., 2004, 6042 A)
NP-protein conjugation by electrostatic
interactions B) conjugation adsorption of NPs
on natural or C) synthetic thiol groups of the
protein immobilization AuSR (Whitesides
) D) conjugation by use of bioaffinity
interactions upon .streptavidin-biotin
binding, E) or antibody-antigen associations
.
Hans-Jörg Schneider Highlights from 50 Years
Biosynthetic Supramolecular Chemistry
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Molecular Recognition with Microarrays Nucleic
acid hybridization DNA /RNA annealing of single
strands A. Rich 1960 DNA chips and
microarrays for genotyping and expression
DNA-Microarrays Fodor 1980 ff Affymetrix
Genechip Q27a molecular basis of the
recognition ? Q28b what binding strength is
expected for GC compared to AT ? how
can it differ ? ( s. Jorgensen J. Am. Chem. Soc.
1990, 2008 )
38.000 probe spotted oligonucleotide(e.g. 25-mer)
microarray Analysis Bioinformatics....
Protein-Microarrays - protein-protein
interactions / Antibody microarrays Small
molecule microarrays (SMMs) - screening of
combinatorial libraries MacBeath, Schreiber,
Schultz
Hans-Jörg Schneider Highlights from 50 Years
Biosynthetic Supramolecular Chemistry
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Artificial photosynthetic systems / Light energy
conversion Q28a which structural elements are
needed ? Why ? Q28b what are the major
challenges ? Reviews Balzani et al Chem. Rev.
1996, 96, 759 Sauvage et al Chem. Soc. Rev.
1999, 28, 293 Gust, D. Moore, T. A. Moore, A.
L. Acc. Chem. Res. 2001,40 Flamigni,
Collin,Sauvage, Acc. Chem. Res. 2008, 857 .
Flamigni, Collin,Sauvage, Acc. Chem. Res. 2008,
857
porphyrin as photosensitizer
gtferricenium ion
longest lifetime of charge-separated state 1.6
s (DMF, 163 K) /quantum yield 34, (lifetime in
bacteriochlorophyll radical cation ca. 1
s) Guldi, Imahori et al J. Phys. Chem. A, 2004 ,
541
gt fullerene radical anion
Hans-Jörg Schneider Highlights from 50 Years
Biosynthetic Supramolecular Chemistry
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Artificial Muscles - Supramolecular chemistry
with polymers recognition sites in
chemomechanical polymers gt stimulation by
external effector (guest ) compounds Q29a
required properties of the polymer ? how to
improve response speed (Q29b) and sensitivity
(Q29c) ? Schneider et al in Intelligent
Materials (2008) J. Mat. Chem. (2008)
(a), (b) Hydrogel expansion
uni-directional
Chitosan hydrogel 10 mM AcOH
950 volume increase
(c), (d) Hydrogel contraction / e.g. for
drug release
Hans-Jörg Schneider
Highlights from 50 Years Biosynthetic
Supramolecular Chemistry
30
Answers to the questions ( possible answers !
)   Q1a why so few practical applications
? Science in these years was more oriented
towards fundamentals and theory Q1b why are
Cramers papers often forgotten ? Cramer changed
this field too early ( he became big shot in
nucleic acid chemistry ) Q3 not enough (native
)enzymes alternatives ? a) enzyme
mutants b) catalytic antibodies
(drawbacks ?) always a problem (also for synth
enzymes) product binding /saturation- what to do
? remove products , eg in flow reactors Q3a
Change of Regioselectivity why ? The hard
oxygen side of the NO2 anions accumulate at N
centers, leading to more soft
soft-combination /alkylation ( pure speculation
!) Q3b Change of Speed why ? concentration
and vicinity effect - the NO2 anions accumulate
at N centers, close to guest better (Km)
value Q4a Diastereoselectivity increase why
? Diene and dienophile in restricted orientation
inside cavity which unpredictable Q4b Rate
increase max. only 70 why ? Only
concentration and vicinity effect (Km value) , no
special TS stabilization Q4c Chiral induction
only 21 - how to improve ? Make CD cavity
less symmetrical, e.g. by monosubstitution at the
rim Q5a origin of the stereoselectivity
? Orientation of edcucts by coordination at the
Mg, and by stacking and/or C-H hydrogen bonds
Q6a what is the drawback ? Very special
binding groups (Adamantanes) must be there
Q6b why is RNA hydrol faster than of DNA
? The 2-OH group in ribose allows formation of
the cyclic intermediate Q7a any practical
applications ? removal of warefare ( biocide
agents etc Q7b role of metalion
? Coordination improves Km, Lewis catalysis
stabilization of phosphate leaving group
of naphthyl units ? stacking improves Km
Q7c adanvantage of Ln instead of e.g. Zn ions?
Higher charge density improves Lewis catalysis
stabilization of phosphate leaving group
Q7d role of metalion ? Coordination improves
Km, Lewis catalysis stabilization of phosphate
leaving group Q8a role of metalion ?
Coordination improves Km, Lewis catalysis
stabilization of phosphate leaving group
Q8b why 2 ions? One can act for Lewis
catalysis, the other for stabilization of
phosphate leaving group Q8c how does it
work ? Both Imidazole and COOH can help
hydrolysis mechanisms Q8d identify role of
the diffent amínoacids The His and Ser can help
hydrolysis mechanisms , these the others can
bind metal ions
Hans-Jörg Schneider Highlights from 50 Years
Biosynthetic Supramolecular Chemistry
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Q9a the basis of the selectivity ?
Watson-Crick base pairing Q9b analytical
method ? Sequence analysis by electrophoretic
separation, after 32-P labeling autoradiography
Q9c adanvantage of Ce4 instead of e.g. Zn2
ions? Higher charge density improves Lewis
catalysis stabilization of phosphate leaving
group Q10a drawback of the substrate ? Very
special binding groups (Adamantanes) must be
there Q10b which metal ions work ? Fe, Mn
Q10c why so many F ? Protect against
(self-)oxidation Q13a practical use of
Biotin-Avidin interaction ? Countless- for
immobilization of almost everything (e.g. on
surfaces- bionanotechnology etc) Q13b why so
high affinity ? Multivalent binding (chelate
effect ) mostly hydrogen bonds Q13c why is
small TDS so unusual ? Usually strong binding
leads to more loss of mobility Q14a theor. reason
for Selectivity-Affinity Correlation ? If DG
increases also the differences DDG between two
complexes should increase, but see next Q14b why
more scatter ? Theory 14a only holds if no
addtl groups (e.g. substituents at the host)
contribute much to the selectivity Q14c why less
selective than calix-crown ? In calix crown the
binding space /cavity if more confined Q15a
Role of Cu? Why Cu ? Large coordination sphere
of Cu, Cu(II) binds well with Imidazole N Q15b
which interaction mechanisms ? Besides hydrogen
bonding to crown stacking of Phe and
porphyrin Q16a which detection method ? Besides
NMR UV (with MV) Q16b other host ? wide
enough cavities with good binding (eg. larger
cyclodextrins or cyclophanes) Q16c why
fluorescence emission upon complexation? The
quenching by crown oxygen e-lone pairs is removed
by complex with NH3 Q16d which interaction
mechanisms ? hydrogen bonds with crown, ion
pairing with COO-, stacking/hydrophobic effect
with Phe etc if present Q16e performance in other
solvents than water ? hydrogen bonds AND ion
pairing would increase stronger binding, but
stacking /hydrophobic effect will decrease
less selectivity Q19a which mechanism dominates
? Stacking / hydrophobic binding Q19b which
measuring method ? UV eg. with porphyrin Soret
band Q21 what is the binding mechanism ?
hydrogen bonds , mostly Hogsteen type Why so
high affinity ? Multivalent binding (chelate
effect ) mostly hydrogen bonds
Hans-Jörg Schneider Highlights from 50 Years
Biosynthetic Supramolecular Chemistry
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Q22a what binding interaction ? ion pairing
with groove phosphates Q22b origin of difference
between DNA and RNA ? RNA has deeper groove with
higher charge density better binding Q24a
identify all binding contributions Stacking
between substrates, hydrogen bonding with
aminoacid residues Q24b identify all binding
contributions Mostly cation- p- binding Q27a
molecular basis of the recognition ? Hydrogen
bonding Q28b what binding strength is expected
for GC compared to AT ? GC has 3, AT only 2
Watson-Crick hydrogen bonds thus GC should
bind 50 better, but it differs how can it
differ ?( s. Jorgensen JACS 1990, 2008)
secondary electrostatic interactions lower GC (
DAA-AAD.) Q28a which structural elements are
needed ? Why ? Electron donor and acceptor,
condcuting spacer, antenna for light
absorption Q28b what are the major challenges
? High quantum yield and long lifetime at
ambient temperature Q29a required properties
of the polymer ? Flexibility, shape memory for
reversibility, insolubility , mechanic stability
Q29b how to improve response speed? Increase
surface to volume of the particle (e.g.
micro/nanoparticles, or thin film) Q29c how to
improve sensitivity ? a) increase binding
affinity , b) decrease volume of particles less
binding sites require less guest molecules
from the surrounding medium ( compartmentalization
effect)-
Hans-Jörg Schneider Highlights from 50 Years
Biosynthetic Supramolecular Chemistry