Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification esterifications acylations halogenations Additions O FG PS PS NMe 3 PS O NN O OMe RO PS NO 2 O O R PS Li O N H Br O HN O NH O H 2 N NH O Br
Polymers as reagentsOther polymer supported reagents
Substitutions:Mitsunobu reactions
etherificationesterifications
acylationshalogenations
Additions
O
FGPS
PS
NMe3
PSO
N N
O
OMeRO
PS
NO2
O
OR
PS Li
O
NH
Br
O HN
O
NH
OH2N
NH
O
Br
Polymers as catalystsCatalysts for reductions
FGPS
PS
TiClCl
Pd (0)
C
C
H2CC
H2
(PPh2)nRhL3-nCl
O OOOCH3
Rh(I)
NN
N
NR
R
Pd(0) R=H
PdCl2 R=CH2CH2CN
Polymers as catalystsAsymmetric catalysts
SO2
FGPS
PS
NO
BH
O
PS O
N N
OMn
ClPS
* *
PSN
H3C
CH3
HO
PSNH
O
OHOH
O
HN PS HO
HOOO
O
OO
O
OOH
O O
O
OOH
OH
OO
Polymer as reagents and catalystsTotal synthesis
Pr NHN
1)
2)
EtOBr
O
N NPNN
NH2
95 %
Pr NN
O
OEt
NMe3 CN
EtOH, cat. AcOH
92 %
Pr NH
NO
OEt
CN
1) Oxidation
2) NCO
70 - 90 %
Pr NN
O
OEt
CNN NP
NN
EtOH
92 %
NN
Pr NH2
O
OEtNH3/MeOH
Quant.N
N
Pr NH2
O
NH2
I
Polymer as reagents and catalystsTotal synthesis
NN
SO2
OEt
N
O
HN
N NN
HO
O
NN
N
OH
NP
N NBr
PF6
NN
N
O
O OEt
O
OR O2SN
N
NCONN
Pr NH2
O
NH2
I
1) 2)
O OEt
O2SN
N
NN
Pr
HN
O NH2 EtOH/NaOEt
MW 10 min @ 120 oC
OEt
O2SN
N
N
NNN
O
Pr
SildenafilViagra TM
82 %
Polymer supported reagents for purificationScavengers for nucleophiles
Entry Resin Co-reagent Reagent type quenched
1
NCO
1o and 2o amines
2
CHO
1o amines
3
COCl
1o and 2o amines
4
NH NH
NH2
O
FF
FF
O
O
1o and 2o amines Anilines
5
O
O O
1o amines
selectively in the presence of 2o
amines
Polymer supported reagents for purificationScavengers for electrophiles
Entry Resin Co-reagent Reagent type quenched
1
NH2
Isocyanates, acid
chlorides, sulphonyl chlorides.
2
NH N
NH2
H2N
Isocyanates, acid chlorides, sulphonyl chlorides, aldehydes, alkyl chloroformates.
3
SO3H
N
NH2
Isocyanates
4
HN SH
Alkylating agents
5
HNNH2
S
α-haloketones
6
N
O
acids
Purification by polymerisation of impuritiesPolyureas
Cl
ClO
Cl RNH2 (excess)
Cl
ClO
NHRRNH3Cl RNH2
NCO
NCO
1) (excess) 2) H2N NH
HN N
H
HN NH2
HN NHO
NHR O HN
N
H2N
NH
NNH
NH
OHN
HN
O
NH
OCl
OHN
Insoluble polyurea(removed by filtration)
Purification by polymerisation of impuritiesROMP
O
O
N N
O
O
PPh2
ROH RNuRNu
PhRuPCy3
PCy3
ClCl
12
1 + 2P(O)Ph2
O
O
NH
NH
O
O
O
O
NH
NH
O
O Ru
Ph
PCy3
PCy3
ClCl
ROMP
Removed by filtration
Soluble polymer supportsPEG
HOO
OH
n
n=100 to 450
PEG
HOO
OH
n
R1HNO
OHR2
DCC
R1HNO
OR2
PEG Peptide synthesis
MeOO
O
n O
Br
R
R= H, NO2
MeOO
O
n O
NH
R
R= Br, NH2
Soluble polymer supportsPEG
MeOO
O
n O
IStille reaction
(nBu)3SnR, Pd cat.
MeOO
O
n O
R
+ R-R
1) Precipitation, filtration
2) Transesterification (MeOH)
MeO
O
R
MeOO
O
n O
HN
SO2Cl
RNH2 MeOO
O
n O
HN
SO2NHR
Synthesis of libraries
1) Precipitation, filtration
2) Basic cleavage
H2N
SO2NHR
Soluble polymer supportsOther soluble supports
n
FGPS
n
nOH
PVA
NH n
H2N NH2
PEI
n
OHO
PAAc
n
OH2N
PAAm
O
OH
O
OHHO
n
Cellulose
OH
PAA
Soluble polymer supportsDendrimer and hyperbranched supports
NN
O
NH
NHO
HN O
HN
O
N
N
N
N
NH
NH
HN
HN
HN
HN
NH
NH
O O
O
O
O
O
O O
HN NH
HN
NH
NH
HN
HN
NH
O
O
O
O
O
O
O
OHOH
OH
OH
OH
OH
O
HO
HO
OH
Soluble polymer supportsDendrimer and hyperbranched supports
OO
H2NO
O
HN
O O
OO
HN
O
NH
MeOO
HN
O
NH
OH
Soluble polymer supportsDendrimer and hyperbranched supports
O
OO O
O OH
O
O
O
HO
OHO
O
O
O
OH
O
O OH
OHO
HOO
OOH
HO
OHO
HO
Hyperbranched Polyglycerol (PG)
1)
2) OsO4 (cat.)
ClPG
OOH
OH
OPG
PG
OOH
Cl PG
HO
OHHO
OOHBase
O
OO O
O
OOH
O
PGO CHO PG
ONHR
Lecture 5• On- and off-bead analysis
o Chemical• Microanalysis• Titration
o Spectroscopic• UV• Fluorescence• IR• MS• NMR
o Issues for Screening
Quantitative UV TitrationThe rapid determination of the absolute amount of hydroxyl or carboxyl groups directly on resin support is possible based on specific reactions between reagent 9-anthroylnitrile or 1-pyrenyldiazomethane (PDAM) and resin-bound hydroxyl or carboxyl groups. After the reaction, the remaining reagent molecules in the supernatant are quantitatively determined by UV-visible spectroscopy. The quantitation can be accomplished by analysing 2-10 mg of resin sample in 30-60 min down to 0.05 mmol/g of resin.
Quantitative UV Titration UV-visible absorption spectra of 9-anthroylnitrile and the 9-anthroylnitrile/quinuclidine adduct. Spectrum 1 is the UV absorption spectrum of 9-anthroylnitrile at a concentration of 1.46 × 10-4 M. Spectrum 2 is the absorption spectrum of the 9-anthroylnitrile/quinuclidine adduct. The concentrations of 9-anthroylnitrile and quinuclidine were 1.46 × 10-4 and 5.25 × 10-4 M.
X-ray Photoelectron Spectroscopy
X-ray Photoelectron Spectroscopy
X-ray photoelectron survey spectra for resins 1, 3, 5, and 6. The elements in the polymer-bound compounds can be readily identified by determining the binding energies of the photoelectron peaks.
X-ray Photoelectron Spectroscopy
Reaction progress. The XP spectra were taken from resin 3 at 0, 5, 10, 20, 30, 50, and 120 min after the initiation of esterification. The full formation of 3 was indicated by the stoichiometric atomic ratio of 1.
Optical Analysis
Optical Analysis
Optical Analysis
Optical Analysis
IR• On-bead
o Gel stateo Solid stateo Single beado Reaction monitoringo Spatially addressable (FTIR microscope)
• Off-beado Identical to solution phase
Single Bead FTIR
IR spectra from a single bead taken at specified times during the course of reaction I. The carbonyl peak at 1740 cm-1 is highlighted with the dotted line. The peak at 1658 cm-1 is from residual solvent DMF. The irregular intensity of this peak may be due to the insufficient drying and the different solvent-adsorbing property of the individual bead.
Single Bead FTIR
The time course of reaction I. The progression of the absorbance at 1740 cm-1 was plotted against time. The solid line is the best fit time course with k = 5 × 10-4 s-1.
Single Bead FTIR
Single Bead FTIR
Single Bead FTIR
IR spectra taken from a single bead at various times in the course of the first step in Scheme 1. Spectra were taken from a single flattened bead at 0, 20, and 40 min after the initiation of the reaction. All spectra were taken using the transmission mode at room temperature. The hydrogen-bonded and unbondedhydroxyl stretches at 3464 and 3579 cm-1 disappear as the ester band (1737 cm-1) and theSi-Ph and Si-O (1426 and 1105 cm-1) stretching signals increase.
On the right: IR spectra taken from a single bead at various times in the course of the third step. Spectra were taken from a single flattened bead at 0, 2, 4, 8, 20, 40, and 80 min after the initiation of the oxidation reaction. The hydrogen-bonded and unbonded hydroxyl stretches near 3490 cm-1 disappear as the band for the aldehyde C-H (2721 cm-1) stretching increases.
Photoacoustic FTIR
Figure 1 FTIR spectra of Merrifield's resin: (a) PA-FTIR; (b) FTIR of KBr pellet.
Photoacoustic FTIR
(a-e) PA-FTIR spectra of resino compounds 1-5.
Synthesis of Resino Dehydroalanine 5
Mass Spectrometry• On-bead
o Ion beam (strong ionisation source required)o Ionisation an issue
• Off-beado All standard techniques available
(+ -hyphenated (e.g. GC))• MALDI, FAB, Electron spray (nanospray), EI etc.
o Chemically cleaved (prior)o Photochemically cleaved (in situ)o Powerful o Spatially addressable (bead location known)
NMR spectroscopy• On-bead
o 1H, 13C, 19Fo Gel and Solid state NMRo Magic Angle Spinning (MAS) o Nanoprobeo Pulsed field gradient (PFG)o New pulse sequences and other experimental conditions
• Off-beado “the usual”
1H Gel NMR
Polyether Resinso PEG-crosslinked
vs PEG-grafted• 1H NMR differences
1H Gel NMR
Partial 500 MHz 1H HRMAS NMR spectra of resin-bound intermediates
5a (A, Ellman's dihydropyran resin),
5b (B, Wang resin),
5c (C, NovaSyn TG resin), and 5d (D, POEPOP resin) swollen in CDCl3, and partial 400 MHz 1H NMR spectrum of compound 11 (E, solution) in CDCl3, showing the trimethylsilyl group chemical shift.