Nucleophilic substitution reactions solvent effects

For carbon-carbon bond-formation purposes, S 2 nucleophilic substitutions are frequently used. Simple S 2 nucleophilic substitution reactions are generally slower in aqueous conditions than in aprotic organic solvents. This has been attributed to the solvation of nucleophiles in water. As previously mentioned in Section 5.2, Breslow and co-workers have found that cosolvents such as ethanol increase the solubility of hydrophobic molecules in water and provide interesting results for nucleophilic substitutions (Scheme 6.1). In alkylations of phenoxide ions by benzylic chlorides, S/y2 substitutions can occur both at the phenoxide oxygen and at the ortho and para positions of the ring. In fact, carbon alkylation occurs in water but not in nonpolar organic solvents and it is observed only when the phenoxide has at least one methyl substituent ortho, meta, or para). The effects of phenol substituents and of cosolvents on the rates of the competing alkylation processes... 

Solvent effects, reaction coordinates, and reorganization energies on nucleophilic substitution reactions in aqueous solution, 38, 161... 

The direction and extent of the effect of solvent polarity on reaction rates of nucleophilic substitution reactions are summarized by the Hughes-Ingold rules, shown in Table 1.9 [26], These rules do not account for the entropic effects or any specific solvent-solute interactions such as H-bonding, which may lead to extra stabilization of reactants or transition states [27],... 

Table 1.9 Hughes-Ingold rales for solvent effects in nucleophilic substitution reactions [27, 28]...

The mechanistic aspects of nucleophilic substitution reactions were treated in detail in Chapter 5 of Part A. That mechanistic understanding has contributed to the development of nucleophilic substitution reactions as importantl synthetic processes. The SN2 mechanism, because of its predictable stereochemistry and avoidance of carbocation intermediates, is the most desirable substitution process from a synthetic point of view. This section will discuss the role of SN2 reactions in the preparation of several classes of compounds. First, however, the important role that solvent plays in SN2 reactions will be reviewed. The knowledgeable manipulation of solvent and related medium effects has led to significant improvement of many synthetic procedures that proceed by the SN2 mechanism. 

Alkyl azides. Sodium azide as such is of little use for preparation of alkyl azides by nucleophilic substitution reactions because of solubility problems. The reaction can be carried out under phase-transfer conditions with methyltrioctylam-monium chloride/NaN3.3 An even more effective polymeric reagent can be obtained by reaction of NaN3 with Amberlite IR-400.4 This reagent converts alkyl bromides, iodides, or tosylates into azides at 20° in essentially quantitative yield. The solvents of choice are CH3CN, CHC13, ether, or DMF. 

Short-lived organic radicals, electron spin resonance studies of, 5, 53 Small-ring hydrocarbons, gas-phase pyrolysis of, 4, 147 Solid state, tautomerism in the, 32, 129 Solid-state chemistry, topochemical phenomena in, 15, 63 Solids, organic, electrical conduction in, 16, 159 Solutions, reactions in, entropies of activation and mechanisms, 1, 1 Solvation and protonation in strong aqueous acids, 13, 83 Solvent effects, reaction coordinates, and reorganization energies on nucleophilic substitution reactions in aqueous solution, 38, 161 Solvent, protic and dipolar aprotic, rates of bimolecular substitution-reactions in,... 

Solvent effects, reaction coordinates, and reorganization energies on nucleophilic substitution reactions in aqueous solution, 38, 161 Solvent, protic and dipolar aprotic, rates of bimolecular substitution-reactions in, 5,173 Solvent-induced changes in the selectivity of solvolyses in aqueous alcohols and related mixtures, 27, 239... 

This helped to derive the Hughes-Ingold rules for predicting the effect of solvent polarity on the reaction rate.1 We have used the combined QM-MOVB/MM method to study three nucleophilic substitution reactions in aqueous solution, which are summarized below. 

The study of reactions of isolated ions and molecules in the gas phase without interference from solvents has led to very surprising results. Gas-phase studies of proton-transfer and nucleophilic substitution reactions permit the measurement of the intrinsic properties of the bare reactants and make it possible to distinguish these genuine properties from effects attributable to solvation. Furthermore, these studies provide a direct comparison of gas-phase and solution reactivities of ionic reactants. It has long been assumed that solvation retards the rates of ion-molecule reactions. Now, using these new techniques, the dramatic results obtained make it possible to show the extent of this retardation. For example, in a typical Sn2 ion-molecule reaction in the gas phase, the substrates react about 10 times faster than when they are dissolved in acetone, and about 10 ( ) times faster than in water cf. Table 5-2 in Section 5.2). 

These Hughes-Ingold rules can be used for making qualitative predictions about the effect of solvent polarity on the rates of all heterolytic reactions of known mechanisms. For nucleophilic substitution reactions of types (5-11) and (5-12)... 

Qualitative Theory of Solvent Effects on Reaction Rates 165 Table 5-4. Predicted solvent effects on rates of nucleophilic substitution reactions [16, 44-46],... 

It should be mentioned that a solvent change affects not only the reaction rate, but also the reaction mechanism (see Section 5.5.7). The reaction mechanism for some haloalkanes changes from SnI to Sn2 when the solvent is changed from aqueous ethanol to acetone. On the other hand, reactions of halomethanes, which proceed in aqueous ethanol by an Sn2 mechanism, can become Sn 1 in more strongly ionizing solvents such as formic acid. For a comparison of solvent effects on nucleophilic substitution reactions at primary, secondary, and tertiary carbon atoms, see references [72, 784]. 

Neglecting solvent effects is extremely hazardous. Equilibria and kinetics can be dramatically altered by the nature of the solvent For example, the rate of nucleophilic substitution reactions spans 20 orders of magnitude in going from the gas phase to polar and nonpolar solvents. A classical example of a dramatic solvent effect on equilibrium is the tautomerism between 1 and 2. In the gas phase, the equilibrium lies far to the left, while in the solution phase, 2 dominates because of its much larger dipole moment." Another classical example is that the trend in gas-phase acidity of aliphatic alcohols is reverse of the well-known trend in the solution phase in other words, in the solution phase, the relative acidity trend is R3COH < R2CHOH < RCH2OH, but the opposite is true in the gas phase. ... 

The effect of a solvent on the rate of the two-step aromatic nucleophilic substitution reactions of primary or secondary amines are sometimes complicated by the acid-base equilibrium (30) and by the fact that the transition state,... 

Solvent isotope effects in general base-catalyzed and nucleophilic substitution reactions... 

I. Lee, Nucleophilic Substitution Reactions of Benzyl Benzene-sulfonates with Anilines in MeOH-MeCN Mixtures-I. Effects of Solvent and Substituent on the Transition-state Structure, Tetrahedron, 1985, 41, 2635. 

Table 3.1 shows the effect of solvent polarity on four different nucleophilic substitution reactions. Creation or destruction of charge gives the biggest effects spreading or dispersal of charge as in the second and third examples in the table gives smaller effects. Molecular and radical reactions do not involve charge build-up in the transition state, and are little affected by solvents thus a check for the presence or absence of a solvent effect often allows a distinction to be made between radical or molecular mecha-... 

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