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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 reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

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Page 1: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

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

Page 2: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

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

Page 3: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

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

Page 4: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

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

Page 5: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

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 %

Page 6: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

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

Page 7: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

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

Page 8: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

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)

Page 9: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

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

Page 10: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

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

Page 11: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

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

Page 12: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

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

Page 13: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

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

Page 14: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

Soluble polymer supportsDendrimer and hyperbranched supports

OO

H2NO

O

HN

O O

OO

HN

O

NH

MeOO

HN

O

NH

OH

Page 15: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

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

Page 16: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

Lecture 5• On- and off-bead analysis

o Chemical• Microanalysis• Titration

o Spectroscopic• UV• Fluorescence• IR• MS• NMR

o Issues for Screening

Page 17: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

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.

Page 18: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

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.

Page 19: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

X-ray Photoelectron Spectroscopy

Page 20: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

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.

Page 21: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

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.

Page 22: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

Optical Analysis

Page 23: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

Optical Analysis

Page 24: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

Optical Analysis

Page 25: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

Optical Analysis

Page 26: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

IR• On-bead

o Gel stateo Solid stateo Single beado Reaction monitoringo Spatially addressable (FTIR microscope)

• Off-beado Identical to solution phase

Page 27: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

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.

Page 28: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

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.

Page 29: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

Single Bead FTIR

Page 30: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

Single Bead FTIR

Page 31: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

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.

Page 32: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

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.

Page 33: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

Photoacoustic FTIR

Figure 1 FTIR spectra of Merrifield's resin: (a) PA-FTIR; (b) FTIR of KBr pellet.

Page 34: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

Photoacoustic FTIR

(a-e) PA-FTIR spectra of resino compounds 1-5.

Synthesis of Resino Dehydroalanine 5

Page 35: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

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)

Page 36: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

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”

Page 37: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

1H Gel NMR

Page 38: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)
Page 39: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

Polyether Resinso PEG-crosslinked

vs PEG-grafted• 1H NMR differences

Page 40: Polymers as reagents - Imperial College London Supports for... · Polymers as reagents Other polymer supported reagents Substitutions: Mitsunobu reactions etherification ... (PDAM)

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.