310 CHAPTER EIGHT Nucleophilic Substitution We saw in Section 8.2 that the rate of nucleophilic substitution depends strongly on the leaving group--alkyl iodides are the most reactive, alkyl fluorides the least. In the next section, we'll see that the structure of the alkyl group can have an even greater effec 8.6 STERIC EFFECTS IN SN2 REACTIONS There are very large differences in the rates at which the various kinds of alkyl halides- methyl, primary, secondary, or tertiary--undergo nucleophilic substitution. As Table 8.2 shows for the reaction of a series of alkyl bromides Br Alkyl bromide Lithium iodide Alkyl iodide Lithium bromide the rates of nucleophilic substitution of a series of alkyl bromides differ by a factor of over 10 when comparing the most reactive member of the group(methyl bromide) and the least reactive member (tert-butyl bromide) The large rate difference between methyl, ethyl, isopropyl, and tert-butyl bromides reflects the steric hindrance each offers to nucleophilic attack. The nucleophile must approach the alkyl halide from the side opposite the bond to the leaving group, and, as illustrated in Figure 8.3, this approach is hindered by alkyl substituents on the carbon that is being attacked. The three hydrogens of methyl bromide offer little resistance to approach of the nucleophile, and a rapid reaction occurs. Replacing one of the hydro- gens by a methyl group somewhat shields the carbon from attack by the nucleophile and causes ethyl bromide to be less reactive than methyl bromide. Replacing all three hydro- gen substituents by methyl groups almost completely blocks back-side approach to the tertiary carbon of (CH3)3CBr and shuts down bimolecular nucleophilic substitution. In general, SN2 reactions exhibit the following dependence of rate on substrate structure ncreasing rate of substitution by the sn2 mechanism R3 CX R,cHX RCHoX CHaX Tertiary Least reactive Most reactive most crowded least crowded TABLE 8.2 Reactivity of Some Alkyl Bromides Toward Substitution by the SN2 Mechanism* Alkyl bromide Structure Class Relative ratet Methyl bromid Unsubstituted 221,00 Ethyl bromide CH3 CH2 Br 1,350 Isopropyl bromide (CH3)2CHBr econdary tert-Butyl bromide (CH3)3CBr Too small to measure *Substitution of bromide by lithium iodide in TRatio of second-order rate constant k for indicated alkyl bromide to k for isopropyl bromide at 25C. Back Forward Main MenuToc Study Guide ToC Student o MHHE WebsiteWe saw in Section 8.2 that the rate of nucleophilic substitution depends strongly on the leaving group—alkyl iodides are the most reactive, alkyl fluorides the least. In the next section, we’ll see that the structure of the alkyl group can have an even greater effect. 8.6 STERIC EFFECTS IN SN2 REACTIONS There are very large differences in the rates at which the various kinds of alkyl halides— methyl, primary, secondary, or tertiary—undergo nucleophilic substitution. As Table 8.2 shows for the reaction of a series of alkyl bromides: the rates of nucleophilic substitution of a series of alkyl bromides differ by a factor of over 106 when comparing the most reactive member of the group (methyl bromide) and the least reactive member (tert-butyl bromide). The large rate difference between methyl, ethyl, isopropyl, and tert-butyl bromides reflects the steric hindrance each offers to nucleophilic attack. The nucleophile must approach the alkyl halide from the side opposite the bond to the leaving group, and, as illustrated in Figure 8.3, this approach is hindered by alkyl substituents on the carbon that is being attacked. The three hydrogens of methyl bromide offer little resistance to approach of the nucleophile, and a rapid reaction occurs. Replacing one of the hydro￾gens by a methyl group somewhat shields the carbon from attack by the nucleophile and causes ethyl bromide to be less reactive than methyl bromide. Replacing all three hydro￾gen substituents by methyl groups almost completely blocks back-side approach to the tertiary carbon of (CH3)3CBr and shuts down bimolecular nucleophilic substitution. In general, SN2 reactions exhibit the following dependence of rate on substrate structure: Least reactive, most crowded Most reactive, least crowded Tertiary R3CX  Secondary R2CHX  Primary RCH2X  Methyl CH3X Increasing rate of substitution by the SN2 mechanism Alkyl bromide RBr Lithium iodide LiI Lithium bromide LiBr Alkyl iodide RI acetone 310 CHAPTER EIGHT Nucleophilic Substitution TABLE 8.2 Reactivity of Some Alkyl Bromides Toward Substitution by the SN2 Mechanism* Alkyl bromide Methyl bromide Ethyl bromide Isopropyl bromide tert-Butyl bromide CH3Br CH3CH2Br (CH3)2CHBr (CH3)3CBr Structure Unsubstituted Primary Secondary Tertiary Class 221,000 1,350 1 Too small to measure Relative rate† *Substitution of bromide by lithium iodide in acetone. † Ratio of second-order rate constant k for indicated alkyl bromide to k for isopropyl bromide at 25°C. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website