Solid-phase synthesis reaction kinetics

One of the cornerstones of combinatorial synthesis has been the development of solid-phase organic synthesis (SPOS) based on the original Merrifield method for peptide preparation [19]. Because transformations on insoluble polymer supports should enable chemical reactions to be driven to completion and enable simple product purification by filtration, combinatorial chemistry has been primarily performed by SPOS [19-23], Nonetheless, solid-phase synthesis has several shortcomings, because of the nature of heterogeneous reaction conditions. Nonlinear kinetic behavior, slow reaction, solvation problems, and degradation of the polymer support, because of the long reactions, are some of the problems typically experienced in SPOS. It is, therefore, not surprising that the first applications of microwave-assisted solid-phase synthesis were reported as early 1992 [24],... 

Fluoroarene-Cr(CO)2L complexes 33p [L = CO, PPh3, P(OPh)3, P(pyrrolyl)3, P(pyrolyl)2 (NMeBn)], where L is a potential linker ligand for solid-phase synthesis, have been evaluated with regard to the rates of nucleophilic substitution by amines [35]. The preparative and kinetic results indicate that SNAr reactions on tris(pyrrolyl)phosphine-modified fluoroar-enechromium complexes proceed rapidly and with high efficiency, and are thus appropriate for the development of solid-phase versions for use in combinatorial synthesis (Scheme 18). 

The fact that the reaction rates in solid phase synthesis are not drastically reduced, compared to the homogeneous reactions, indicates that the diffusion of the reagent into the polymeric matrix is not a limiting factor for the method. This has been confirmed by Andreatta and Rinkll9) in kinetic studies on both cross-linked and linear polystyrenes. This means that the intrinsic problems of solid phase synthesis arise from deviations in the linear kinetic course in the final stages of reaction due to non-equivalence of functional groups. 

Most of the polymeric reagents which have been developed so far make use of an insoluble cross-linked polymer as the backbone. Investigations on the reaction rates and kinetic course in solid-phase synthesis revealed that the reaction sites within the polymeric matrix are chemically and kinetically not equivalent, making quantitative conversions almost impossible. Furthermore, the difficulty in the preparation and accessibility of insoluble polymeric reagents appears to limit a more... 

Synthesis on solid supports was first developed by Merrifield [1] for the assembly of peptides. It has expanded to include many different applications including oligonucleotide, carbohydrate, and small-molecule assembly (see Chapters 11 and 14). The repetitive cycle of steps involved in the solid-phase synthesis of biopolymers can be performed manually using simple laboratory equipment or fully automated with sophisticated instrumentation. This chapter examines typical solid-phase reaction kinetics to identify factors that can improve the efficiency of both manual and automated synthesis. The hardware and software features of automated solid-phase instruments are also discussed. The focus of this discussion is not on particular commercial model synthesizers but on the basic principles of instrument operation. These considerations can assist in the design, purchase, or use of automated equipment for solid-phase synthesis. Most contrasting features have advantages and disadvantages and the proper choice of instrumentation depends on the synthetic needs of the user. 

The field of solid-phase synthesis instrumentation is continually advancing. Improvements in synthesis reagents, reaction monitoring, and instrument hardware and software will extend the limits of the instrumentation. As synthesizer capabilities improve, there is the potential that more and more control will be taken from the user until the instrument becomes a black box. It is important, however, to maintain an understanding of the principles of instrument operation and the chemistry that is being performed. The instrument is secondary to the chemistry but is an essential tool to help carry out the synthesis efficiently. The best instrument cannot improve ineffective chemistry and, conversely, a poorly designed instrument can compromise a very efficient chemical process. As long as the basic principles of reaction kinetics, fluid mechanics, and instrument safety are sustained, a solid-phase synthesizer can be used to its maximum potential and benefits. 

In another paper, a development of the microwave-assisted parallel solid-phase synthesis of a collection of 21 polymer-bound enones was described. The two-step protocol involves initial high-speed acetoacetylation of polystyrene resins with a selection of seven common P-ketoesters. When microwave irradiation at 170 °C was employed, complete conversions were achieved within 1-10 min, a significant improvement over the conventional thermal method, which takes several hours for completion. Significant rate enhancements were also observed for the subsequent microwave-heated Knoevenagel condensations. Reaction times were reduced to 30-60 min at 125 °C in the microwave protocol compared to 1-2 days using conventional thermal conditions. Kinetic comparative studies indicate that the observed rate enhancements can be attributed to the rapid direct heating of the... 

Enantioselective ring opening of epoxides was attained with (salen)Cr(III) complex (191) [68]. Cyclopentene derivatives (190) were converted with Me3SiN3 to azide-alcohols (192) in 80-90% yields up to 98% ee (Scheme 16.56). Kinetic resolution of racemic styrene oxide was performed in 98% ee. This reaction was applied to practical synthesis of enantiopure cyclic 1,2-aminoalcohols by reduction of the azide products by Pt02-catalyzed hydrogenation [69], to synthesis of cyclopentenone derivatives [70] to formal synthesis of bioactive compound Balanol [71], and to solid-phase synthesis of peptides [72]. 

An important tool for the fast characterization of intermediates and products in solution-phase synthesis are vibrational spectroscopic techniques such as Fourier transform infrared (FTIR) or Raman spectroscopy. These concepts have also been successfully applied to solid-phase organic chemistry. A single bead often suffices to acquire vibrational spectra that allow for qualitative and quantitative analysis of reaction products,3 reaction kinetics,4 or for decoding combinatorial libraries.5... 

The one-pot dynamic kinetic resolution (DKR) of ( )-l-phenylethanol lipase esterification in the presence of zeolite beta followed by saponification leads to (R)-l phenylethanol in 70 % isolated yield at a multi-gram scale. The DKR consists of two parallel reactions kinetic resolution by transesterification with an immobilized biocatalyst (lipase B from Candida antarctica) and in situ racemization over a zeolite beta (Si/Al = 150). With vinyl octanoate as the acyl donor, the desired ester of (R)-l-phenylethanol was obtained with a yield of 80 % and an ee of 98 %. The chiral secondary alcohol can be regenerated from the ester without loss of optical purity. The advantages of this method are that it uses a single liquid phase and both catalysts are solids which can be easily removed by filtration. This makes the method suitable for scale-up. The examples given here describe the multi-gram synthesis of (R)-l-phenylethyl octanoate and the hydrolysis of the ester to obtain pure (R)-l-phenylethanol. 

High temperatures are generally needed in solid state synthesis to improve reaction rates and to facilitate solid state diffusion. Solid state diffusion is typically very slow. Thus, mechanical grinding steps are important to homogenize the sample and encourage complete reaction. It is important to realize, however, that some phases decompose at elevated temperatures. For example, Ba CujOy is unstable above about 1050°C (1) and the related phase, BajYCUjOg is only stable to 860°C in one atmosphere of oxygen (2). Thus, efforts to prepare these phases require a balance between the heat put in to speed the reaction kinetics and the stability limits of the desired phase. 

The most important characteristics that make fluorous synthesis superior to solid-supported synthesis is the favorable reaction kinetics associated with the solution-phase reactions. Comparison reactions using fluorous vs. solid-supported thiols to scavenge a bromide are shown in Fig. 1 [16]. Using 1.5equiv of F-thiol 1, more than 95% bromide was quenched in less than 40 min (top line). Under the same conditions and using 1.5 equiv PS-thiol 2, only 50% of the halide was quenched after 80 min (bottom line). By doub-... 

An important difference between solution-phase and solid-phase chemistry is the new variable the polymer support. The polymer has significant influence on the reaction. There have been many solid supports used over the years with variation in polymer type, degree of cross-linking, and even quality. These factors have significant influence on solvation properties and reaction kinetics, and hence on synthesis characteristics. Various grafted polymers may have characteristics that differ from other supports. Consequently, the optimal conditions for a reaction on one polymer may be different from those for the same reaction on a different polymer. This should not dishearten the chemist. A reported reaction may be used as the basis for optimization studies of the reaction on a different support. Variables such as solvent, temperature, and reaction time may all be investigated to optimize the reaction on the new surface. 

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