Very polar aprotic solvents

The most commonly encountered of these are dimethyl sulphoxide (DMSO) and N,N-dimethylformamide (DMF). With these solvents it is often possible to remove most if not all by adding the quenched reaction mixture to a relatively large volume of water, and extracting this several times with ether. The combined organics are then washed with more water. Any remaining DMF or DMSO will need to be removed in further purification of the crude product. 

Some reactions use hexamethylphosphoramide (HMPA) as an additive, which can be difficult to remove. HMPA can be extracted from an organic solution by washing with aqueous lithium chloride or bromide provided that the solvent for the organic solution is not chlorinated. 

With the extractions completed the organic extract needs to be dried. A lot of the dissolved water can be removed by extracting with saturated brine and it is advisable to do this. The organic extract is then dried fully by 

The solvent is now usually removed using a rotary evaporator, with the final traces being removed using a high vacuum line. Beware when using the high vacuum line, if your product is volatile it will disappear into the traps  

At this stage it is very useful (after weighing ) to examine the crude product by ir, nmr, and tic before proceeding with purification as this will give you an idea as to the state of purity amongst other things. The next chapter is given over to methods for purification of the crude product. 

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The solvation property of the cations of this very polar aprotic solvent can make some salts more stable. Therefore, aluminium, sodium, mercury or silver perchlorate solutions are explosive. The same goes for iron (III) nitrate solutions. 

The SfjAr reaction between thiolates and monofluorobenzme and its derivatives requires high temperatures and polar aprotic solvents [19, 20, 21. Polyfluoroaro-matics show very little selectivity for fluoiine replacement [22, 2J] (equation 13). 

We consider first the Sn2 type of process. (In some important Sn2 reactions the solvent may function as the nucleophile. We will treat solvent nucleophilicity as a separate topic in Chapter 8.) Basicity toward the proton, that is, the pKa of the conjugate acid of the nucleophile, has been found to be less successful as a model property for reactions at saturated carbon than for nucleophilic acyl transfers, although basicity must have some relationship to nucleophilicity. Bordwell et al. have demonstrated very satisfactory Brjinsted-type plots for nucleophilic displacements at saturated carbon when the basicities and reactivities are measured in polar aprotic solvents like dimethylsulfoxide. The problem of establishing such simple correlations in hydroxylic solvents lies in the varying solvation stabilization within a reaction series in H-bond donor solvents. 

Aromatic denitrocyclizations have been used for many years in some well-known synthetic reactions. Probably the best known example is the Turpin synthesis of phenoxazines and similar synthesis of phenothiazines. The classical setup used usually base-catalyzed reactions in polar protic solvents, very often alcohols. In many cases using polar aprotic solvents was found advantageous. Besides the mentioned influence of the H-bonding, better ionization and lower solvation of the nucleophile are also important. Sf Ar reactions proceed through strongly polarized complexes, which are well soluble and highly polarized in polar aprotic solvents. 

Especially for large-scale work, esters may be more safely and efficiently prepared by reaction of carboxylate salts with alkyl halides or tosylates. Carboxylate anions are not very reactive nucleophiles so the best results are obtained in polar aprotic solvents45 or with crown ether catalysts.46 The reactivity order for carboxylate salts is Na+ < K+ < Rb+ < Cs+. Cesium carboxylates are especially useful in polar aprotic solvents. The enhanced reactivity of the cesium salts is due to both high solubility and minimal ion pairing with the anion 47 Acetone is a good solvent for reaction of carboxylate anions with alkyl iodides48 Cesium fluoride in DMF is another useful... 

Polar aprotic solvents dissolve ionic compounds, and they solvate cations very well. 

In polar aprotic solvents the nucleophile is only very slightly solvated and is, consequently, highly reactive. 

In non-polar aprotic solvents like chlorobenzene and CH2CI2, these are virtually unsolvated and unshielded (except by their counterions) and are consequently very reactive. Therefore, the etherification takes place in solution the reaction is very fast at room tempera -ture and the reaction course can be followed by the disappearance of the green color of the phenolate anion. 

The reactions discussed in the following sections take place in aprotic solvents, and reference to known or estimated thermodynamic basicities will relate to DM SO unless otherwise noted, since DM SO is the polar aprotic solvent in which most thermodynamic acidities have been measured [55-58]. Values of pK determined in DM SO can usually be assumed to parallel values in DMF [59, 60], MeCN, and other polar aprotic solvents whereas pK values (and relative pK values) related to water and other hydroxylic solvents can be very different. 

For adequate reaction rates, a high concentration of iodide anion is necessary. The cation portion of the salt appears to have little or no effect on catalytic activity or reaction selectivity. Inorganic iodides (such as potassium iodide) are the obvious first choice based on availability and cost. Unfortunately these catalysts have very poor solubility in the reaction mixture without added solubilizers or polar, aprotic solvents. These solubilizers (e.g., crown ethers) and solvents are not compatible with the desired catalyst recovery system using an alkane solvent. Quaternary onium iodides however combine the best properties of solubility and reactivity. 

With regard to SN2 reactions, the solvent can affect profoundly the reactivity of a given nucleophile. Thus anions such as Cl and CNe, which are weakly nucleophilic in hydroxylic solvents and in poor ionizing solvents such as 2-propanone (acetone), become very significantly nucleophilic in polar aprotic solvents such as (CH3)2SO. The reason is that for salts such as NaCl and NaCN the aprotic solvent preferentially solvates the cation, leaving the anion relatively bare. This dissociation of the anion from the cation together with its poor solvation makes the anion abnormally reactive as a nucleophile. 

There are numerous ways to determine experimentally pK values of chemical compounds (205). Classical methods are potentiometric titration and ultraviolet (UV) spectroscopy, among others. These techniques have been widely applied for nucleobases and also for metal-nucleobase complexes. For the extremes such as negative pK values (pK < —2) of singly or multiply protonated nucleobases, or very high pK values (pK >15) for deprotonation of exocyclic amino groups of nucleobases (C, G, A), modifications have to be employed. These include the consideration of the Hammett acidity function in superacidic solvents or solvent mixtures (206), as well as extrapolative techniques according to Bunnett-Olsen and Marziano-Cimino-Passerini to be applied in polar, aprotic solvents (45, 207). 

Figure 7 shows the degradation quantum yield, d of a-guaiacoxyacetoveratrone in 7 deaerated solvents acetonitrile (ACN), dioxane (DIOX), 1,2-dimethoxyethane (DME), methanol (MeOH), ethanol (EtOH), isopropanol (iPrOH) and ethoxyethanol (EtOEtOH) (40,41). The 4 was significantly larger in alcohols, 0.34 to 0.52, than in pure aprotic solvents, < 0.1. There was very little difference in d in polar aprotic solvents, 0.08 in acetonitrile, compared to that in non-polar aprotic solvents,... 

The surface films react chemically with solution species, thus leading to their dissolution as reaction products [17]. Surface species such as oxides, hydroxides, and nitrides may be highly nucleophilic, while many polar aprotic solvents are highly electrophilic. Hence, chemical dissolution of pristine surface films on active metals in solutions is a very probable route [18]. 

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