Solution-phase chemistry

Solid-phase chemistry is an efficient synthetic tool that, compared with solution-phase chemistry, simplifies the work-up of the reaction, allows the process to be driven to completion by using excess of reagents, and can be automatized [2a]. In recent years, many studies have been devoted to developing both surface-mediated and resin-supported synthesis. Today the solid-phase approach is not limited to peptides and oligonucleotides but is also used to synthesize molecules of lower molecular weight. 

Soluble support-based synthetic approaches offer the advantages of both homogeneous solution-phase chemistry (high reactivity, ease of analysis) and solid-phase synthesis (large excess of reagents, simple product isolation and purification) [98,99]. As a representative example, PEG, one of the most widely used soluble polymers, has good solubility in most organic solvents (i.e., dichloromethane, acetonitrile, dimethylformamide, and toluene), but it... 

RASP Polymer-assisted solution-phase chemistry... 

An important breakthrough in that respect was the use of soHd-phase organic synthesis (SPOS) where the attachment of the substrate to an insoluble support allowed for easy workup (filtration) and for rapid generation of products via split-mix procedures [1,2]. An important subsequent development consisted of the immobihzation of reagents, scavengers and catalysts. This technique, coined polymer-assisted solution phase chemistry (PASP), allowed solution phase synthesis of compoimds, yet still enjoying the bene-... 

DCC is a waxy solid that is often difficult to remove from a bottle. Its vapors are extremely hazardous to inhalation and to the eyes. It should always be handled in a fume hood. The isourea by-product of a DCC-initiated reaction, dicyclohexyl urea (DCU) (Figure 3.5), is also water-insoluble and must be removed by organic solvent washing. For synthesis of peptides or affinity supports on insoluble matrices this is not a problem, because washing of the support material can be done without disturbing the conjugate coupled to the support. For solution phase chemistry, however, reaction products must be removed by solvent washings, precipitations, or recrystallizations. 

Reaction scale-up using the Voyager system in genuine continuous-flow format is achieved by the use of special coiled flow-through cells. The reaction coils are made of glass or Teflon (Fig. 3.24) with a maximum flow rate of 20 mL min-1 and operational limits of 250 °C or 17 bar. The continuous-flow format should only be used for homogeneous solution-phase chemistry, as slurried mixtures may cause prob-... 

Kirschning A, Monenschein H, Wittenberg R (2001) Functionalized polymers - emerging versatile tools for solution-phase chemistry and automated parallel synthesis. Angew Chem Int Ed 40 650-679... 

With the following examples, we will investigate and discuss the following (a) Scale-up phenomena of different solid phase reactions and the corresponding on-bead analytics (b) the effect of loading (an equivalent to concentration in solution-phase chemistry) (c) comparison with the solution-phase alternative and (d) the synthesis and use of new trityl linkers. 

Without the experience and the equipment to perform solid-phase supported syntheses on a larger scale, chemists explore alternative routes utilising solution-phase chemistry. To compare the direct scale-up on solid support and to evaluate the advantages and disadvantages of both approaches, pyrimidine 1 was prepared in solution phase as well. For this relatively small and simple molecule, similar chemistry was applied (see Scheme 3) with some interesting results arising. 

J. P. Whitten, Y. E Xie, P. E. Erickson, T. R. Webb, E. B. De Souza, D. E. Grigoriadis, J. R. McCarthy, Rapid Microscale Synthesis, a New Method for Lead Optimization Using Robotics and Solution Phase Chemistry Application to the Synthesis and Optimization of Corticotropin-Releasing Factor Receptor Antagonists , J. Med. Chem. 1996,39, 4354-4357. 

In addition to describing an alternative to aqueous phase work-up, a novel approach to solution phase chemistry was shown using bifunctional or tagged re-... 

The future of solid supported solution phase chemistry will continue to generate many exciting developments. Only in recent years have we truly perceived what might be possible to achieve with these systems in multi-step organic synthesis. Building upon this knowledge platform we believe it is certainly possible to use... 

The design of powerful new linker strategies is crucial to the advancement of technologies used for combinatorial chemistry on polymeric supports. They are usually derived from protecting groups known for solution-phase chemistry [6, 18]. 

The multicomponent reactions have been widely used in solid and solution-phase chemistry during the last years. Multicomponent reaction strategies offer significant advantages compared with conventional liner type syntheses. Three or more reactants come together in a one pot reaction to form new products that contain portions of all the components [281]. There are several well-known multicomponent reactions that have been used in combinatorial chemistry. 

Indeed, immobilization of catalysts to a sohd phase involves various advantages over conventional solution-phase chemistry... 

In principle, linker groups are polymer-enlarged versions of blocking functions used in regular solution-phase chemistry. Therefore, enzymatic transformations that may be employed for the removal of protecting groups in solution, in principle may also open up alternative opportunities for releasing compounds from polymeric supports. The linkers developed so far can be divided into exo- and endo-linkers (Fig. 10.1) cleavable by exo- respectively endo-enzymes, as proposed by Flitsch et al. [6]. 

The experiments carried out by Moss and his associates >30 years ago, which triggered the research in this field and can be regarded as landmarks, reveal that reactions of arylcarbenes with solidified alkenes at 77 K are completely different from those expected based on well-established fluid solution-phase chemistry. 

Figure 11.5. The magnitude of ko s decreases with decreasing temperature until 170 K, whereupon it reaches a value of 3.2 x 10 s. Below this temperature, koBs remains constant. " The breakpoint in the Arrhenius plot is 180-200 K, which is in exactly the same temperature range in which the solution phase chemistry changes from the trapping of ketenimine 30 with diethylamine to the dimerization of 33t. Thus, the low-temperature data of Figure 11.5 were associated with k]sc, the rate constant for intersystem crossing of singlet to triplet phenylnitrene, and the high temperature data with k., the rate constant for rearrangement of 33t.

Palladium-catalyzed transformations greatly enhance the scope of solid-phase synthetic chemistry. A number of fundamental pharmacophores are accessible through a variety of reliable manipulations that may be performed in high yield under mild conditions. This area continues to grow, as solution-phase chemistry is adapted to provide better methods for carbon-carbon bond formation in combinatorial chemistry. We view these advances as central to the field and look forward to future developments. 

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