LON-CAPA Sn2

Nucleophilic Aliphatic Substitution Reactions

The Sn2 Mechanism

Nucleophiles

Introduction

We have seen how chemical kinetics allows chemists to evaluate the impact that changing the substituents attached to the reaction center has on the rates of Sn2 reactions. Now we will hold the structure of the substrate constant and examine changes in reaction rates that accompany changing the nucleophile.

Scheme 1 reiterates the general description of nucleophilic aliphatic substitution reactions.

Scheme 1

Nucleophilic Aliphatic Substitution

Changing Nucleophiles

A large variety of compounds are potentially nucleophilic. Wherever possible, the discussion that follows attempts to minimize the structural variations that cause differences in nucleophilic reactivity. First we will consider a series of nucleophiles in which the nucleophilic atom is always an oxygen. The data presented was reported in an article entitled "Kinetics and Free Energy Relationships of Reactions of Methyl Nitrate with Nucleophiles in Water" in the journal Acta Chemica Scandinavica 25 (1971) 3367-3372. Scheme 2 summarizes one group of reactions that was studied.

Scheme2

Sn2 Reactions of Methyl Nitrate

Figure 1 shows a plot of the logarithm of the second order rate constants against the pK_a values of the conjugate acids of the nucleophiles used in the reactions outlined in Scheme 1.

Figure 1

Whaddya Know, More pK_a

Exercise 1 Write an equation like the one shown in Scheme 2 for each nucleophile in Figure 1.

Exercise 2 Draw the structure of the conjugate acid of each of the nucleophiles in Figure 1.

Exercise 3 Select the strongest acid: acetic acid, CH₃CO₂H hydrogen phosphate, HPO₄^-2

Exercise 4 Select the weakest base: acetate ion, CH₃CO₂^- phosphate ion, PO₄^-3

Exercise 5 Select the poorest nucleophile: acetate ion, CH₃CO₂^- phosphate ion, PO₄^-3

Exercise 6 State the correlation between the changes in base strength and nucleophilic reactivity for the ions shown in Figure 1: For reagents in which the nucleophilic atom is an oxygen, the nucleophilic reactivity increases as the strength of the base .

Exercise 7 Would you expect hydroxide ion to be more nucleophilic or less nucleophilic than phosphate ion?

The relative nucleophilicities of the halide ions depend dramatically upon the solvent. For the reaction shown in Equation 1, the rate constants are 4.2 x 10^-4, 6.6 x 10^-4, and 7.9 x 10^-4sec^-1mol^-1L, when the nucleophile is ^-:F, ^-:Cl^*, and ^-:Br, respectively. The solvent system was 70% water and 30% acetone. Here, ^-:Cl^* represents isotopically labeled chlorine.

Exercise8 Would you expect the rate constant for reaction 1 to be greater than or less than 7.9 x 10^-4sec^-1mol^-1L, when the nucleophile is ^-:I?

Exercise 9 Calculate the relative reactivities of bromide, chloride, and fluoride ions from the rate constants given above.

Equation 2 describes a series of Sn2 reactions in which the cation associated with the halide ion as well as the solvent were changed. The relative rates of substitution for several reactions are summarized in Table 1.

Table 1

It All Depends....

Reagent	Solvent	F^-	Cl^-	Br^-	I^-
Na⁺X^-	Acetone/H₂O	0.53	0.8	1	...
Na⁺X^-	CH₃OH	...	0.019	0.13	1
(CH₃CH₂CH₂CH₂)₄N⁺X^-	Acetone	...	18.4	4.9	1
Li⁺X^-	Acetone	...	0.2	0.9	1
Li⁺X^-	DMF	...	9.1	3.4	1
(CH₃CH₂CH₂CH₂)₄N⁺X^-	DMSO	1667	7.9	3.4	1
(CH₃CH₂CH₂CH₂CH₂)₄N⁺X^-	None	...	620	7.7	1

The the presence of four alkyl groups in the tetraalkyl ammonium cations reduces the association between the cation and its anion, presumably making the anion more available to react with an electrophilic center. The last entry in Table 1 deserves explanation. The reaction involved is shown in Equation 3 for the specific case where X equals Cl.

In this reaction, the tetraalkyl ammonium halide acts as both a source of the nucleophile and as the substrate. No solvent is used, so the assumption is that the halide ions display their "inherent" nucleophilic reactivity.

Equation 4 describes an interesting experiment in which the investigators compared the rates of Sn2 reactions of methyl p-toluenesulfonate with LiCl, LiBr, and LiI in a mixture of pyridine (C₅H₅N) and dimethylformamide (DMF), two dipolar, aprotic solvents. Figure 2 presents the data in graphical form.

Figure 2

Nothin's Ever Simple

Exercise 10 The melting points of LiI, LiBr, and LiCl are 446, 550, and 605^oC, respectively. Which anion is most tightly associated with the lithium cation? iodide bromide chloride

Exercise 11 As the concentration of the lithium halide increases, the association between the cation and anion . As the association between the cation and anion increases, the nucleophilic reactivity of the anion should .

Exercise 12 Rationalize the fact that chloride ion reacts faster than iodide ion at concentrations below 0.1M, but that iodide ion reacts faster than chloride ion at concentrations above 0.3M.

Exercise 13 In aqueous solution, the order of nucleophilic reactivity of the halide ions is I > Br >Cl >F. (The melting point of LiF, by the way, is 845^oC.) Which ion would you expect to have the greatest charge-dipole interactions with water? iodide bromide chloride fluoride