Solvents aprotic, substitution, nucleophilic

Other measures of nucleophilicity have been proposed. Brauman et al. studied Sn2 reactions in the gas phase and applied Marcus theory to obtain the intrinsic barriers of identity reactions. These quantities were interpreted as intrinsic nucleo-philicities. Streitwieser has shown that the reactivity of anionic nucleophiles toward methyl iodide in dimethylformamide (DMF) is correlated with the overall heat of reaction in the gas phase he concludes that bond strength and electron affinity are the important factors controlling nucleophilicity. The dominant role of the solvent in controlling nucleophilicity was shown by Parker, who found solvent effects on nucleophilic reactivity of many orders of magnitude. For example, most anions are more nucleophilic in DMF than in methanol by factors as large as 10, because they are less effectively shielded by solvation in the aprotic solvent. Liotta et al. have measured rates of substitution by anionic nucleophiles in acetonitrile solution containing a crown ether, which forms an inclusion complex with the cation (K ) of the nucleophile. These rates correlate with gas phase rates of the same nucleophiles, which, in this crown ether-acetonitrile system, are considered to be naked anions. The solvation of anionic nucleophiles is treated in Section 8.3. 

A difficulty that occasionally arises when carrying out nucleophilic substitution reactions is that the reactants do not mix. For a reaction to take place the reacting molecules must collide. In nucleophilic substitutions the substrate is usually insoluble in water and other polar solvents, while the nucleophile is often an anion, which is soluble in water but not in the substrate or other organic solvents. Consequently, when the two reactants are brought together, their concentrations in the same phase are too low for convenient reaction rates. One way to overcome this difficulty is to use a solvent that will dissolve both species. As we saw on page 450, a dipolar aprotic solvent may serve this purpose. Another way, which is used very often, is phase-transfer catalysis ... 

The reactivity of triflate-substituted pyridopyrrolizines has been investigated. In the presence of a polar aprotic solvent and a nucleophile, these compounds undergo Sn reactions, leading to the a-substituted 3//-3-pyrrolones. This process is thought to involve loss of the trifluoromethanesulfinate ion, formation of an acyliminium ion intermediate, and nucleophilic attack on the latter <1995JOC5382> (Scheme 44). 

The reactivity of 02 - with alkyl halides in aprotic solvents occurs via nucleophilic substitution. Kinetic studies confirm that the reaction order is primary > secondary > tertiary and I > Br > Cl > F for alkyl hahdes, and that the attack by 02 - results in inversion of configuration (Sn2). Superoxide ion also reacts with CCI4, Br(CH2)2Br, CeCle, and esters in aprotic media. The reactions are via nucleophilic attack by 02 on carbon, or on chlorine with a concerted reductive displacement of chloride ion or alkoxide ion. As with all oxyanions, water suppresses the nucleophilicity of 02 (hydration energy, lOOkcalmoL ) and promotes its rapid hydrolysis and disproportionation. The reaction pathways for these compounds produce peroxy radical and peroxide ion intermediates (ROO and ROO ). 

Cyclic ethers have an O atom in a ring. A common cyclic ether is tetrahydrofuran (THF), a somewhat polar aprotic solvent used in nucleophilic substitution (Section 7.8C) and many other organic reactions. 

In reactions of tertiary halides, unimolecular processes dominate in protic solvents (especially water and aqueous solvent mixtures) where substitution is usually faster than elimination. Substitution involves nucleophilic attack directly at a cationic center, whereas elimination involves removal of an acidic hydrogen two bonds removed from the cationic atom, explaining the difference. Clearly, a nucleophilic species is strongly attracted to the most positive center and that should lead to the major product. In aprotic solvents, bimolecular substitution is not observed for tertiary halide due to the high energy required to form the pentacoordinate transition state (sec. 2.7.A.i). Under conditions that favor bimolecular reactions and in the presence of a suitable base, elimination is the dominant process. 

Classes of Solvents. Table 8.6 lists a number of solvents in which nucleophilic substitutions are carried out and classifies them according to two criteria whether they are protic or aprotic, and polar or nonpolar. 

The nucleophilicity of anions, in general, depends very much on the degree of solvation. Much of the data that form the basis for quantitative measurement of nucleophilicity is for reactions in hydroxylic solvents. In protic, hydrogen-bonding solvents, anions are subject to strong interactions with solvent. Hard nucleophiles are more strongly solvated by protic solvents than soft nucleophiles, and this difference contributes to the greater nucleophilicity of soft anions in such solvents. Nucleophilic substitution reactions often occur more readily in polar aprotic solvents than they do in protic solvents. This is because anions are weakly solvated in such... 

Solvent effects on nucleophilic aromatic substitutions are similar to those discussed for Sn2 reactions. Dipolar aprotic solvents, crown ethers, and phase... 

For a secondary halide in a reaction with a base, with water as the solvent, ionization is a competitive process. Most of the time, the 8 2 is faster than the Sf fl reaction because direct attack at the a-carbon is more facile than ionization, but the extent of direct substitution versus ionization and then trapping with a nucleophile depend on the strength and nature of the nucleophile. If the nucleophile is a weak base, the Sn2 reaction will dominate in an aprotic solvent. If the nucleophile is a strong base, elimination competes with substitution, and a mixture of Sn2 and E2 products is predicted. In water, it is not obvious whether ionization will lead to the major product, although it is assumed that in aqueous media the 8 1 reaction will dominate. 

The solvent in which nucleophilic substitutions are carried out has a marked effect on relative nucleophilicities. For a fuller understanding of the role of the solvent, let us consider nucleophilic substitution reactions carried out in polar aprotic solvents and in polar protic solvents. An organizing principle for substitution reactions is the following ... 

Solvent Selection The choice of dipolar aprotic solvent for aromatic nucleophilic substitution reactions is a very complicated one. 

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... 

The large rate enhancements observed for bimolecular nucleophilic substitutions m polai aprotic solvents are used to advantage m synthetic applications An example can be seen m the preparation of alkyl cyanides (mtiiles) by the reaction of sodium cyanide with alkyl halides... 

Rate increases with increasing po larity of solvent as measured by its dielectric constant e (Section 8 12) Polar aprotic solvents give fastest rates of substitution solvation of Nu IS minimal and nucleophilicity IS greatest (Section 8 12)... 

Nucleophilic Substitution Route. Commercial synthesis of poly(arylethersulfone)s is accompHshed almost exclusively via the nucleophilic substitution polycondensation route. This synthesis route, discovered at Union Carbide in the early 1960s (3,4), involves reaction of the bisphenol of choice with 4,4 -dichlorodiphenylsulfone in a dipolar aprotic solvent in the presence of an alkaUbase. Examples of dipolar aprotic solvents include A/-methyl-2-pyrrohdinone (NMP), dimethyl acetamide (DMAc), sulfolane, and dimethyl sulfoxide (DMSO). Examples of suitable bases are sodium hydroxide, potassium hydroxide, and potassium carbonate. In the case of polysulfone (PSE) synthesis, the reaction is a two-step process in which the dialkah metal salt of bisphenol A (1) is first formed in situ from bisphenol A [80-05-7] by reaction with the base (eg, two molar equivalents of NaOH),... 

The realization that die nucleophilicity of anions is strongly enhanced in polar aprotic solvents has led to important improvements of several types of synthetic processes that involve nucleophilic substitutions or additions. 

Neopentyl (2,2-dimethylpropyl) systems are resistant to nucleo diilic substitution reactions. They are primary and do not form caibocation intermediates, but the /-butyl substituent efiTectively hinders back-side attack. The rate of reaction of neopent>i bromide with iodide ion is 470 times slower than that of n-butyl bromide. Usually, tiie ner rentyl system reacts with rearrangement to the /-pentyl system, aldiough use of good nucleophiles in polar aprotic solvents permits direct displacement to occur. Entry 2 shows that such a reaction with azide ion as the nucleophile proceeds with complete inversion of configuration. The primary beiuyl system in entry 3 exhibits high, but not complete, inversiotL This is attributed to racemization of the reactant by ionization and internal return. 

Nucleophilic displacement reactions One of the most common reactions in organic synthesis is the nucleophilic displacement reaction. The first attempt at a nucleophilic substitution reaction in a molten salt was carried out by Ford and co-workers [47, 48, 49]. FFere, the rates of reaction between halide ion (in the form of its tri-ethylammonium salt) and methyl tosylate in the molten salt triethylhexylammoni-um triethylhexylborate were studied (Scheme 5.1-20) and compared with similar reactions in dimethylformamide (DMF) and methanol. The reaction rates in the molten salt appeared to be intermediate in rate between methanol and DMF (a dipolar aprotic solvent loiown to accelerate Sn2 substitution reactions). 

Secondary alkyl halides Sjvj2 substitution occurs if a weakly basic nucleophile is used in a polar aprotic solvent, E2 elimination predominates if a strong base is used, and ElcB elimination takes place if the leaving group is two carbons away from a carbonyl group. Secondary allylic and benzyiic alkyl halides can also undergo S l and El reactions if a weakly basic nucleophile is used in a pro tic solvent. 

Other salts, especially fluoride salts, (e.g., KF) can be used to perform nucleophilic substitution. As is well known, halides, and particularly the fluoride anions, are rather powerful Lewis bases and can exert a catalytic effect on aromatic nucleophilic substitutions in dipolar aprotic solvents. Phenols can be alkylated in the presence of KF (or CsF) absorbed on Celite64,65 or Et4NF.66 Taking advantage of this reaction, halophenols and dihalides with bisphenols have been successfully polymerized in sulfolane at 220-280°C by using KF as the base. 

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