Solution-Phase Chemical Synthesis

Solution phase chemical synthesis is a convenient way for making surfactant coated magnetic nanoparticles, as described in various reviews [12-18]. Monodisperse Co nanoparticles with standard deviation less than 10% are synthesized by decomposition of Co2(CO)8 [19-22] or Co(rj3-C8Hi3X n4-C8Hi2) [23] and reduction of cobalt salt [24,25] in the presence of oleic acid and trialkylphosphine, or trialkylphosphine oxide, or alkylamine. Monodisperse iron nanoparticles are normally prepared from decomposition of Fe(CO)5 [26-28]. However, metallic iron-based particles from this decomposition procedure are difficult to characterize due to the chemical instability. A recent synthesis using decomposition of Fe[NSiMe3)2]2 offers a promising approach to monodisperse Fe nanocrystals [29]. 

The above limitations with solid phase chemistries have necessitated the pursuit of solution-phase chemistries for library generation. The advantages of solution-phase syntheses are legion, but the major benefits include unlimited numbers and types of reaction, lower requirements of solvents and reagents compared to solid phase syntheses and that such chemistries can be developed and monitored with relative ease. A conventional solution-phase chemical synthesis involves the use of arrays of sub millimeter wells as discrete reaction vessels to which the reagents are delivered using automated robotic systems. Although such systems have been successful, the batch nature of... 

As shown above, the optimized combination of precursors (C0Q2, Co(CH3COO)2 or Co2(CO)8) and reducing agents (superhydride or polyalcohol) allows the selective preparation of monodisperse cobalt nanoparticles with a desired crystalline phase. Such behavior shows that the solution-phase chemical synthesis of magnetic nanocrystals is not thermodynamically controlled, and thus can allow the preparation of crystal phases that are metastable, such as the e-Co structure [9]. The control of size and the crystalline phase of nanoparticles is important, as these parameters greatly affect the magnetic properties (see Section 3.3.2.5). 

Since 1986, when the very first reports on the use of microwave heating to chemical transformations appeared [147,148], microwave-assisted synthesis has been shown to accelerate most solution-phase chemical reactions [24-27,32,35]. The first application of microwave irradiation for the acceleration of reaction rate of a substrate attached to a solid support (SPPS) was performed in 1992 [36]. Despite the promising results, microwave-assisted soHd-phase synthesis was not pursued following its initial appearance, most probably as a result of the lack of suitable instriunentation. Reproducing reaction conditions was nearly impossible because of the differences between domestic microwave ovens and the difficulties associated with temperature measurement. The technique became a Sleeping Beauty interest awoke almost a decade later with the publication of several microwave-assisted SPOS protocols [37,38,73,139,144]. There has been an extensive... 

The approaches used for preparation of inorganic nanomaterials can be divided into two broad categories solution-phase colloidal synthesis and gas-phase synthesis. Metal and semiconductor nanoparticles are usually synthesized via solution-phase colloidal techniques,4,913 whereas high-temperature gas-phase processes like chemical vapor deposition (CVD), pulsed laser deposition (PLD), and vapor transfer are widely used for synthesis of high-quality semiconductor nanowires and carbon nanotubes.6,7 Such division reflects only the current research bias, as promising routes to metallic nanoparticles are also available based on vapor condensation14 and colloidal syntheses of high-quality semiconductor nanowires.15... 

Parlow JJ, Devraj RV, South MS (1999) Solution-phase chemical library synthesis using polymer-assisted purification techniques. Curr Opin Chem Biol 3 320-336... 

Applications of the cross-metathesis reaction in more diverse areas of organic chemistry are beginning to appear in the literature. For example, the use of alkene metathesis in solution-phase combinatorial synthesis was recently reported by Boger and co-workers [45]. They assembled a chemical library of 600 compounds 27 (including cisttrans isomers) in which the final reaction was the metathesis of a mixture of 24 oo-alkene carboxamides 26 (prepared from six ami-nodiacetamides, with differing amide groups, each functionalised with four to-alkene carboxylic acids) (Eq.27). 

Just as improvements have been made in classical solution-phase protein synthesis (see Section 5.1.7), so have important and effective improvements been made in solid-phase synthetic methodology. These improvements have enhanced the ease and speed of synthesis, the quality and yields of products, and the size of proteins accessible to chemical synthesis. [181 Numerous laboratories have studied each of the steps in the solid-phase process and the details of the changes are described in detail in other sections of this volume (see Vol. E22a, Section 4.3). Briefly, the following modifications have been forthcoming ... 

Chemical synthesis Chemical— solution-phase Chemical— solid-phase Chemical—hybrid Potential for scaleup to metric tons Rapid development for small to medinm scale Relatively rapid development cycle potential for scaleup to metric tons Lengthy and costly development, relatively high cost of raw materials and conversion Scalenp potential may be limited relatively high cost of raw materials and conversion Raw materials (resins, amino acid derivatives) currently expensive... 

The first report of resin capture in solution-phase chemical library synthesis involved the covalent capture of solution-phase Ugi reaction products onto a functionalized polystyrene resin.73 Excess reactants, reagents, and reagent byproducts were washed away from the resin-captured intermediates. Further manipulation and release afforded purified solution-phase products for screening. More recently the same group reported on resin capture as a technique for the preparation of tetrasubstituted olefin libraries.74 75 As illustrated in Scheme 5, m-vinyl di-boryl esters were reacted with aryl halides (R3ArX) in parallel Suzuki reactions, leading to solution-phase intermediates. Another Suzuki reaction, this time with the... 

Flynn, D. L. Devraj, R. V. Parlow, J. J. Recent Advances in Polymer-Assisted Solution-Phase Chemical Library Synthesis and Purification, Curr. Opin. Drug Disc. Dev. 1998, 7, 41. 

Gayo, L. M. Suto, M. J. Ion-Exchange Resins for Solution Phase Parallel Synthesis of Chemical Libraries, Tetrahedron Lett. 1997,38, 513. 

Gayo LM, Suto MJ, Ion-exchange resins for solution phase parallel synthesis of chemical libraries, Tetrahedron Lett., 38 513-516, 1997. 

Soluble supports for solution-phase combinatorial synthesis were extensively covered in Section 8.5. A recent survey of available soluble supports, with respect to their use in the soluble supported synthesis of various classes of chemicals (90), highlights the wide range of physicochemical properties (especially regarding solubility, tendency to crystallize, and solubilization power) that are embedded in different polymers and copolymers. The assessment of a sort of S AR for the composition of copol5miers versus their physicochemical properties would require the preparation of a large number of examples. Combinatorial approaches to soluble support libraries could be highly beneficial in this perspective. 

Linclau B, Sing AK, Curran DP. Organic-Fluorous phase switches a fluorous amine scavenger for purification in solution phase parallel synthesis. J Org Chem. 1999 64 2835-2842. Parlow JJ. Polymer-assisted solution-phase chemical library synthesis. Curr. Opin. Drug Discov. Devel. 2005 8 757-775. 

Problems in solution phase peptide synthesis have been largely overcome by the development of solid phase peptide synthesis (SPPS). The chemical principles of peptide link formation and peptide synthesis remain the same, but in SPPS the growing peptide chain is anchored to a solid phase resin, thereby easing the iterative process of peptide bond formation, removing the need for crystallisations and purifications after each step of the synthesis, and in some ways simplifying protection/deprotection problems. SPPS earned Bruce Merrifield a Nobel Prize in 1986, and has eased the technical challenges of peptide synthesis to the extent that the process can now be automated. 

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