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Solid-phase organik syntheses - Burdges K.

Burdges K. Solid-phase organik syntheses - John Wiley & Sons, 2000. - 283 p.
ISBN 0-471-22824-9
Download (direct link): phaseorganicsynthesis2000.pdf
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4.4. ILLUSTRATIVE APPLICATIONS 137
3311
2156 2109
R
R
SiMe3
R
Wavenumber (cm-1)
Figure 4.7. Infrared spectra used to monitor cross-coupling and deprotection reactions on resin-bound phenylacetylene oligomers. Observation of a null at 3311 and 2156 cm-1 corresponds to complete acetylene coupling and trimethylsilylacetylene deprotection, respectively.
formed terminal acetylene is easily identified in a similar manner; bands at 3311 cm-1 (strong) and 2109 cm'1 (weak) correspond to carbon-hydrogen and carbon-carbon bond stretches, respectively. The deprotection step is therefore accompanied by complete disappearance (null signal) of the TMS-acetylene stretch. The reliability of this method was corroborated by the liberation and characterization of oligomers and is approximately sensitive to a detection level of 5% unreacted material. This method was also used to evaluate cleavage of sequences from the solid support by checking for the presence of IR bands attributed to the oligomers themselves.
Other laboratories have used FTIR spectroscopy to determine the kinetics of reactions on different polymer supports39 and to enumerate factors regulating site interactions in different types of supports (see Chapter 7, p. 219).40 A major weak point of the procedure is the need for IR diagnostic functions or changes in hybridization to be involved in the transformation to be investigated. For phenylacetylene oligomers, however, the TMS and terminal acetylene absorptions are ideal.
Both 13C NMR and *H NMR have also been used to monitor solid-phase syntheses. For l3C NMR methodologies, the main concern lies in the thousands of transients needed to properly visualize bead-attached moieties. Recently, a rapid technique has been developed.41 The method takes advan-
138 SOLID-PHASE SYNTHESIS OF SEQUENCE-SPECIFIC PHENYLACETYLENE OLIGOMERS
tage of commercially available NMR tube inserts that position resin within the observation coils of an NMR instrument. Spectra are clear and easily deconvoluted, attributed mainly to the highly characteristic and 13C-en-riched functions involved. As little as 20 mg of support containing less than
1 mg of compound yielded meaningful spectra in as few as 64 transients. For phenylacetylene systems, 13C NMR was used to track the preparation of the rc-propylamination of Merrifield’s resin, a transformation detailed previously. A comparison of the spectra of the chloromethyl polymer and rc-propylaminomethyl polymer indicates complete substitution of the benzyl chloride for the benzyl-rc-propylamino group. These results were verified by a null chlorine percentage in elemental analysis.
lH NMR has also been a valuable monitoring method for SPOS. Reported first in 1994, several uses of magic angle spinning (MAS) to enhance the spectra of suspensions of polymer-supported compounds are now documented.42 More recently, a spin echo twist was added to the MAS technique.43 Selective quenching of the polystyrene signal (often a problem with its broad peaks in the aromatic region) could be achieved by a judicious choice of ò values in a spin echo pulse sequence. Polymer-supported lH NMR two-dimensional spectra have also been obtained; the results from COSY and TOCSY analyses can be highly informative.
4.5. SCOPE AND LIMITATIONS
The final part of this chapter deals with the scope and limitations of solid-phase phenylacetylene-oligomer syntheses. Solution-phase methods have several advantages making it the method of choice in some cases. Larger scales can be realized more easily and rapidly because cumbersomely large amounts of resin are needed to prepare gram quantities of product on a solid phase. Even if the resin is affordable, small mechanical losses in long synthetic procedures can accumulate to be significant. All the common monitoring techniques (TLC, GC, MS) that are used routinely in solution-phase syntheses can only be performed after cleavage of intermediates/product in solid-phase routes. Moreover, yields from solution-phase methods are more reliable because the product is isolated in larger amounts.
Numerous difficulties can arise when calculating yields in solid-phase syntheses.13 Errors in»resin weight, molar concentration of products on the resin, and elemental analysis can be relatively large. Three distinct cases were identified, and these required different methods of yield determination
4.5. SCOPE AND LIMITATIONS 139
TABLE 4.6. Three Possible Yield Calculations for Solid-Phase Syntheses
Case Estimated
Number Tracking Method Equation^ Error
1 Gain of N in product Ó = 1 /[(Ne/Np) (MeN^/E) - /Vsi AM] ±0.13
2 Loss of Cl in product Y = [AM(Np/Ne)E/MeNe] + 1 ±0.29
3 Triazene N in reactant Y= {[1/(1+ AE/E[)\ - 1 }/Nsi AM ±0.92
and product
aY is yield, Ne is the number of moles of tag element, Np is the moles of product, Me is the molecular weight of the tag element (g/mol), Nsi is the moles of starting functionality in 1 g of the initial resin, E is the weight fraction of the tag element (from elemental analysis), AM is the change in molecular weight upon reaction, and AE is the change in the tag element’s weight fraction.
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