Relative Reactivity of Halide Leaving Groups

Among alkyl halides, alkyl iodides undergo nucleophilic substitution at the fastest rate, alkyl fluorides the slowest. 

The order of alkyl halide reactivity in nucleophilic substitutions is the same as their order in eliminations. Iodine has the weakest bond to carbon, and iodide is the best leaving group. Alkyl iodides are several times more reactive than alkyl bromides and from 50 to 100 times more reactive than alkyl chlorides. Fluorine has the strongest bond to carbon, and fluoride is the poorest leaving group. Alkyl fluorides are rarely used as substrates in nucleophilic substitution because they are several thousand times less reactive than alkyl chlorides. 

A single organic product was obtained when l-bronno-3-chloropropane was allowed to react with one nnolar equivalent of sodiunn cyanide in aqueous ethanol. What was this product  

Representative Functional Group Transformations by Nucleophilic Substitution Reactions of Alkyl Halides (Continued) 

Iodide ion ( J ) Alkyl chlorides and bromides are converted to alkyl R- X acetone R — + X  

Iodides by treatment with sodium iodide in acetone. Nal is soluble in Iodide ion Alkyl chloride Alkyl iodide Chloride or 

PROBLEM 8.1 Write a structural formula for the principal organic product formed in the reaction of methyl bromide with each of the following compounds  

SAMPLE SOLUTION (a) The nucleophile in sodium hydroxide is the negatively charged hydroxide ion. The reaction that occurs is nucleophilic substitution of bromide by hydroxide. The product is methyl alcohol. 

Nucleophile and comments General equation and specific example  

Iodide ion (d ) Alkyl chlorides and bromides are converted to alkyl Iodides by treatment with sodium iodide in acetone. Nal is soluble in acetone, but NaCI and NaBr are insoluble and crystallize from the reaction mixture, driving the reaction to completion. / 0 acetone y + R—X R — + Iodide ion Alkyl chloride Alkyl iodide or bromide acetone CH3CHCH3 -h Nal CH3CHCH3 1 1 Br 1 X Chloride or bromide ion + NaBr (solid) 

To ensure that reaction occurs in homogeneous solution, solvents are chosen that dissolve both the alkyl halide and the ionic salt. Alkyl halides are soluble in organic solvents, but the salts often are not. Inorganic salts are soluble in water, but alkyl halides are not. Mixed solvents such as ethanol-water mixtures that can dissolve both the alkyl halide and the nucleophile are frequently used. Many salts, as well as most alkyl halides, possess sigiuh-cant solubility in dimethyl sulfoxide (DMSO) or N, Ai-dimethylformamide (DMF), which makes them good solvents for carrying out nucleophilic substituhon reactions (Section 8.9). 

The use of DMSO as a solvent in elimination reactions was mentioned earlier, in Section 5.14. 

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Functional Group Transformation by Nucleophilic Substitution 307 Relative Reactivity of Halide Leaving Groups 309... 

Oxidative addition is often the rate-determining step and initially gives a cis complex that rapidly isomerizes to its trans-a-palladium(II) complex. The reaction proceeds with the complete retention of configuration for alkenyl halides and with inversion for allylic and benzylic halides. The relative reactivity of leaving groups is I > OTf > Br ... 

Because the first step is the rate-determining step, the rate of an El reaction depends on both the ease with which the carbocation is formed and how readily the leaving group leaves. The more stable the carbocation, the easier it is formed because more stable carbocations have more stable transition states leading to their formation. Therefore, the relative reactivities of a series of alkyl halides with the same leaving group parallel the relative stabilities of the carbocations. A tertiary benzylic halide is the most reactive alkyl halide because a tertiary benzylic cation—the most stable carbocation—is the easiest to form (Sections 7.7 and 10.8). 

Probably both reactant stabilization and the already evaluated relative instability of the cationic transition state contribute to the slowness of the solvolysis of vinyl components, but other factors are certainly involved. The most obvious experimental problem is whether the oompoimds compared react by a unimolecular mechanism or nucleophilic attack by the solvent is involved to a certain extent. In the case of vinylic systems, for instance, nucleophilic solvation from the rear is in general much more hindered than in the case of saturated compounds and the transition state is likely to be stabUized only by electrophilic solvation of the leaving group (Rappoport and Atidia, 1970). The low m values observed in the case of vinyl halides or sulphon-ates may be taken as a strong indication of poor solvation of the transition state in solvolytic reactions of vinyl derivatives. These and other complications, such as differences in hyperconjugation, differences in electronegativity of the —C= and — bonds (Jones and Maness, 1970), make the comparison of the unimolecular reactivity of vinyl and saturated compoimds of little help even for a semi-quantitative evaluation of the relative stabihty of vinyl and alkyl cations. 

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