Organic solvents, drawbacks

Reactions between A -(l-chloroalkyl)pyridinium chlorides 33 and amino acids in organic solvents have a low synthetic value because of the low solubility of the amine partner. A special protocol has been designed and tested in order to circumvent this drawback. Soon after the preparation of the salt, an aqueous solution of the amino acid was introduced in the reaction medium and the two-phase system obtained was heated under reflux for several hours. However, this was not too successful because sulfur dioxide, evolved during the preparation of the salt, was converted into sulfite that acted as an 5-nucleophile. As a result, A -(l-sulfonatoalkyl)pyridinium betaines such as 53 were obtained (Section IV,B,3) (97BSB383). To avoid the formation of such betaines, the salts 33 were isolated and reacted with an aqueous solution of L-cysteine (80) to afford thiazolidine-4-carboxylic acids hydrochlorides 81 (60-80% yields). 

The main drawback of GC is sample introduction and this is especially important when analytes are to be determined at trace levels. Today, however, there is no problem with introducing 10 -100 p.1 of Organic solvents such as ethyl acetate or alkanes... 

Solid-phase microextraction eliminates many of the drawbacks of other sample preparation techniques, such as headspace, purge and trap, LLE, SPE, or simultaneous distillation/extraction techniques, including excessive preparation time or extravagant use of high-purity organic solvents. SPME ranks amongst other solvent-free sample preparation methods, notably SBSE (Section 3.5.3) and PT (Section 4.2.2) which essentially operate at room temperature, and DHS (Section 4.2.2),... 

The drawbacks of the W/O emulsification method include the use of large amounts of oils as the external phase, which must be removed by washing with organic solvents, heat stability problems of drugs, possible interactions of the cross-linking agent with the drug, and, as with all nanoparticles prepared by emulsification techniques, a fairly broad particle size distribution. 

The improvement of its activity and stability has been approach by the use of GE tools (see Refs. [398] and [399], respectively). A process drawback is the fact that the oxidation of hydrophobic compounds in an organic solvent becomes limited by substrate partition between the active site of the enzyme and the bulk solvent [398], To provide the biocatalyst soluble with a hydrophobic active site access, keeping its solubility in organic solvents, a double chemical modification on horse heart cytochrome c has been performed [400,401], First, to increase the active-site hydrophobicity, a methyl esterification on the heme propionates was performed. Then, polyethylene glycol (PEG) was used for a surface modification of the protein, yielding a protein-polymer conjugates that are soluble in organic solvents. 

Similar structures were later employed to create original dendronized polymers 485 and 486, based on a chitosan backbone and using such sialodendrons as 484 (Fig. 50).328 Chitosan itself is nontoxic, biodegradable, and has widespread biological activities, but major intrinsic drawbacks such as low solubility in both organic solvents and water have hampered its development as a bioactive polymer. Thus, the synthesis of water-soluble... 

The reaction mixture is often complicated by condensation of mono-saccharidic molecules yielding unwanted homodisaccharides. This problem is also reduced by the minimum water approach (water activity of ca. 0.7-0.8). The organic solvent at low concentration probably deactivates the enzyme due to structural changes whereas high solvent concentrations with the necessary minimum water cause fixation of the enzyme structure in its active conformation. Unfortunately, glycosidases are rather instable in low-water media. This is a big drawback compared to highly solvent-resistant lipases.94... 

Many drawbacks of conventional polymeric supports, such as hmited solubilities/ sweUabilities in many organic solvents, limited site accessibility and poor loading... 

Lipid particles can also be prepared by dispersing a hot microemulsion in cold water (2 to 3°C) under stirring. Drawbacks of this process are the frequent need for organic solvents and the relative low particle concentration as a result of the dilution with water [14]. 

P25 Each of these [previous methods] involves one or more of the following drawbacks uses expensive and toxic metals, demonstrates severe water sensitivity, or produces hydrazoic acid, which is highly toxic and explosive as well as volatile. The few methods that seek to avoid hydrazoic acid liberation during the reaction, by avoiding acidic conditions, require a very large excess of sodium azide. In addition, ah of the known methods use organic solvents, in particular, dipolar aprotic solvents such as DMF. This is one of the solvent classes that process chemists would rather not use. (Adapted from Demko and Sharpless, 2001)... 

It is remarkable that better enantioselectivities are achieved when CALB-catalyzed acylations of the alcohol are carried out in organic solvent rather than in water. Excellent enantioselectivities are obtained when the process is carried out with vinyl esters [22]. However, in some cases the use of vinyl or alkyl esters as acyl donors has the drawback of the separation of the ester (product) and the alcohol (substrate). A practical strategy to avoid this problem is the use of cyclic anhydrides [23]. In this case an acid is obtained as product, which can be readily separated from the unreacted alcohol by a simple aqueous base-organic solvent liquid-liquid extraction. This methodology has been successfully used for the synthesis of (-)-paroxetine as indicated in Scheme 10.11 [24]. 

Methods have been proposed to miniaturize, speed up and automate the shake-flask approach. The main difficulties in this challenge are the number of time-consuming steps which cannot be totally eliminated and the persistence of well known drawbacks. For example, the mutual saturation and decantation of organic and aqueous phases, or the crucial separation of the two phases after shaking which multiplies the manipulations. Automation of the process is also difficult due to several compound-dependent parameters which have to be rigorously controlled, such as the volume ratio between organic solvent and aqueous phase according to the estimated log P, or the sample concentration. 

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