Nucleophilicity polar protic solvents

Solvent Effects on the Rate of Substitution by the S 2 Mechanism Polar solvents are required m typical bimolecular substitutions because ionic substances such as the sodium and potassium salts cited earlier m Table 8 1 are not sufficiently soluble m nonpolar solvents to give a high enough concentration of the nucleophile to allow the reaction to occur at a rapid rate Other than the requirement that the solvent be polar enough to dis solve ionic compounds however the effect of solvent polarity on the rate of 8 2 reactions IS small What is most important is whether or not the polar solvent is protic or aprotic Water (HOH) alcohols (ROH) and carboxylic acids (RCO2H) are classified as polar protic solvents they all have OH groups that allow them to form hydrogen bonds... 

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. 

In contrast with protic solvents, which decrease the rates of SN2 reactions by lowering the ground-state energy of the nucleophile, polar aprotic solvents increase the rates of Sn2 reactions by raising the ground-state energy of the nucleophile. Acetonitrile (CH3CN), dimethylformamide ((Chy NCHO,... 

Product 34 predominates in the polar aprotic solvent (acetonitrile), while in the polar protic solvent (methanol) products 35 are formed preferentially. The different products are caused by the relative rate of deprotonation against desilylation of the aminium radical, that is in turn governed by the action of enone anion radical in acetonitrile as opposed to that of nucleophilic attack by methanol. In an aprotic, less silophilic solvent (acetonitrile), where the enone anion radical should be a strong base, the proton transfer is favoured and leads to the formation of product 34. In aprotic solvents or when a lithium cation is present, the enone anion radical basicity is reduced by hydrogen bonding or coordination by lithium cation, and the major product is the desilylated 35 (Scheme 4). 

Solvent effects Different solvents have different effects on the nucleophilicity of a species. Solvents with acidic protons are called protic solvents, usually O—H or N—H groups. Polar protic solvents, e.g. dimethyl sulph-oxide (DMSO), dimethyl formamide (DMF), acetonitrile (CH3CN) and acetone (CH3COCH3) are often used in 8 2 reactions, since the polar reactants (nucleophile and alkyl halide) generally dissolve well in them. 

Small anions are more strongly solvated than larger anions, and sometimes this can have an adverse effect. Certain anions, e.g. F , can be solvated so well in polar protic solvents that their nucleophilicity is reduced by the solvation. For efficient 8 2 reactions with small anions, it is usual to use polar aprotic solvents, which do not have any O—H or N—H bonds to form hydrogen bonds to the small anions. 

Pohir protic solvents (polar solvents that can hydrogen bond) stabilize the nucleophile and any carbocation that may form, A stable nucleophile slows SN2 reactions, while a stable carbocation increases the rate of SN1 reactions. Thus polar protic solvents increase the rate of SN1 and decrease the rate of Sw2. Pohr aprotic solvents (polar solvents that can t form hydrogen bonds) do not form strong bonds with ions and thus increase the rate of SN2 reactions while inhibiting SN1 reactions. In SN1 reactions, the solvent is often heated to reflux (boiled) in order to provide energy for the formation of the carbocation. 

B-8. Rank the following species in order of decreasing nucleophilicity in a polar protic solvent (most — least nucleophilic) ... 

An additional factor that plays a role is the character of the solvent. Increasing stabilization of the nucleophile by the solvent results in decreasing reactivity. Thus, polar protic solvents will stabilize the chloride and bromide ions through the formation of hydrogen bonds to these smaller anions. Iodide is a comparatively better nucleophile in these solvents. The reverse behaviour predominates in aprotic polar media. 

The better the solvent stabilizes the ions, the more probable that the reaction will follow an SN1 pathway (e.g., in polar protic solvents such as water/acetone). The more highly substituted is the incipient carbenium ion, the more probable that the reaction will follow an SN1 pathway. The more unreactive the nucleophile, the more probable it becomes that a reaction with secondary and tertiary electrophiles will follow an SN1 pathway. A weaker nucleophile is not as effective in the backside attack, since this location is sterically shielded, especially in the case of tertiary substrates. Carbenium ions are planar and therefore less sterically hindered, and are naturally more reactive as electrophiles than the uncharged parent compound. 

Recommendations on the synthesis of metal phthalocyanines. It is still difficult to evaluate real reaction mechanisms in each synthetic procedure applied. It is clear that the use of such polar protic solvents as alcohols contributes to higher yields of Pc from PN in the electrosynthesis conditions due to the ease of nucleophilic attack of the generated additional RO-. In the further steps of Pc formation from PN or 1,3-D, a solvent s nature has no significant importance. These data about the importance of, first of all, the initial stage correspond to those reported on UV irradiation [40] of PN solutions, where such a treatment is effective only at the beginning of the process. However, in the case of the use of urea and PA, a solvent must be completely inert (or be close to urea s nature) to carry out the one-step synthesis of metal phthalocyanines, in order to exclude any negative influence on the reaction course. The fact that the yields are almost always higher in the case of direct electrosynthesis could serve as an additional confirmation about the usefulness and necessity of this technique. 

Polar protic solvents like water or alcohols can also dissolve ionic reagents but they solvate both the metal cation and the anion. Thus, the anion is caged in by solvent molecules. Thus stabilises the anion, makes it less nucleophilic and makes it less likely to react by the SN2 mechanism. Due to this, the SN1 mechanism becomes more important. 

The SN1 mechanism is specially favoured when the polar protic solvent is also a non-basic nucleophile. Therefore, it is most likely to take place when an alkyl halide is dissolved in water or alcohol. Protic solvents are bad for the SN2 mechanism because they solvate the nucleophile, but they are good for the SN1 mechanism. This is because polar protic solvents can solvate and stabilise the carbocation intermediate. If the carbocation is stabilised, the transition state leading to it will also be stabilised and this determines whether the SN1 reaction is favoured or not. Protic solvents will also solvate the nucleophile by hydrogen bonding, but unlike the SN2 reaction, this does not affect the reaction rate since the rate of reaction is independent of the nucleophile. 

Secondary alkyl halides can undergo both SN2 and E2 reactions to give a mixture of products. However, the substitution product predominates if a polar aprotic solvent is used and the nucleophile is a weak base. Elimination will predominate if a strong base is used as the nucleophile in a polar, protic solvent. In this case, bulky bases are not so crucial and the use of ethoxide in ethanol will give more elimination product than substitution product. Increasing the temperature of the reaction favours E2 elimination over Sn2 substitution as explained above. 

An important lesson from this is that the idea of nucleophilicity in the real world of organic reactions is not easy to pigeonhole. Polarizability is important, but basicity is also very important and can be influenced by solvation. Values of the pKa of a given compound vary as a function of solvent, and so does basicity. You can make a species, anions in particular, more reactive by putting them in solvents that don t solvate them very well. Dipolar aprotic solvents interact nicely with cations, but not so well with anions. Polar protic solvents (e. g., water, alcohols) can hydrogen bond to anions, diminishing their basicity and literally blocking them sterically. 

The answer to this question depends on the solvent used for reaction as illustrated in Figure 3.4. Also relevant is recognition that chloride anions are hard bases and iodide anion are soft bases. Iodide is the better nucleophile in polar protic solvents while chloride is the better nucleophile in polar aprotic solvents. 

Water, alcohols, and carboxylic acids are polar protic solvents able to form hydrogen bonds (hydroxylic solvents). They solvate both cations and anions well. A nucleophilic reagent such as bromide ion must be accompanied by a cation, say, the sodium ion, and hydroxylic solvents dissolve salts such as NaBr by hydrogen bonding to the anion and electron donation to the cation. This is solvation by a polar protic solvent. These solvents do not ionize the salt, which already exists in the solid state as ions they separate and solvate the ions already present. 

Polar protic solvents (curve 1) stabilize the charged transition state by solvation and also stabilize the nucleophile by hydrogen bonding. 

Polar aprotic solvents (curve 2) stabilize the charged transition state by solvation, but do not hydrogen-bond to the nucleophile. Since the energy level of the nucleophile is higher, AG" is smaller and the reaction is faster in polar aprotic solvents than in polar protic solvents. 

Atoms vary greatly in size down a column of the periodic table, and in this case, nucleophilic-ity depends on the solvent used in a substitution reaction. Although solvent has thus far been ignored, most organic reactions take place in a liquid solvent that dissolves all reactants to some extent. Because substitution reactions involve polar starting materials, polar solvents are used to dissolve them. There are two main kinds of polar solvents—polar protic solvents and polar aptotic solvents. 

In polar protic solvents, however, nucleophilicity increases with increasing size of an anion (opposite to basicity). 

Ft3CX (3 ) Sn1 Favored by weak nucleophiles (usually neutral) polar protic solvents... 

Nucleophilicity increases down a column of the periodic table in polar protic solvents (7.8C). 

We have learned that nucleophilicity depends on the solvent when nucleophiles of very different size are compared. For example, in polar protic solvents nucleophilicity follows the trend F < OF < Br < I", but the reverse is true in polar aprotic solvents. Predict the trend in nucleophilicity for these halide anions in the gas phase, with no solvent. 

The same conditions that favor substitution by an S l mechanism also favor elimination by an El mechanism a 3° alkyl halide as substrate, a weak nucleophile or base as reagent, and a polar protic solvent. As a result, both reactions usually occur in the same reaction mixture to afford a mixture of products, as illustrated in Sample Problem 8.2. 

Nucleophilic attack of ammonia or of a primary or secondary amine on an O-alkyl thiocarboxylate (2) provides a formally straightforward approach to thioamides and a number of examples have been reported (equation l). - However, some limitations should be noted. Thus, there is a tendency of esters (2) to rearrange to their 5-alkyl isomers on heating (cf. Volume 6, Chapter 2.5) and these yield amides with amines rather than thioamides. Besides, excess primary amine will lead to amidine formation, or the tetrahedral intermediate of the substitution reaction may break down to an imidate rather than a thioamide (cf. Volume 6, Chapter 2.7). These unwanted side reactions are favoured in polar, protic solvents such as ethanol. In contrast, THF has proven to be particularly useful in the synthesis of tertiary thioamides according to equation (1). For improved reactivity in the preparation of V-aryl derivatives and milder reaction conditions, it is advantageous to employ the amine in the form of its Mg salt. ... 

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