CHAPTER EIGHT Nucleophilic Substitution TABLE 8.3 Effect of Chain Branching on Reactivity of Primary Alkyl Alkyl bromide Structure Relative rate Ethyl bromide CHaCH.Br Propyl bromide Br sobutyl bromide (CH3)2 CHCH2 Br 0.036 Neopentyl bromide (CH3)3CCH2 Br 0.00002 Substitution of bromide by lithium iodide in acetone. Ratio of second-order rate constant k for indicated alkyl bromide to k for ethyl bromide at 25C. 8.7 NUCLEOPHILES AND NUCLEOPHILICITY The Lewis base that acts as the nucleophile often is, but need not always be, an anion Neutral Lewis bases can also serve as nucleophiles. Common examples of substitutions involving neutral nucleophiles include solvolysis reactions. Solvolysis reactions are sub- stitutions in which the nucleophile is the solvent in which the reaction is carried out. Solvolysis in water converts an alkyl halide to an alcohol Water Alkyloxonium halide halide Solvolysis in methyl alcohol converts an alkyl halide to an alkyl methyl ether: H3C、 H3C、 R+ⅹ-- HX H Methyl alcohol Dialkyloxonium halide In these and related solvolyses, the first stage is the one in which nucleophilic substitution takes place and is rate-determining. The proton-transfer step that follows it is much faster. Since, as we have seen, the nucleophile attacks the substrate in the rate determining step of the SN2 mechanism, it follows that the rate at which substitution occurs may vary from nucleophile to nucleophile. Just as some alkyl halides are more reactive than others, some nucleophiles are more reactive than others. Nucleophilic strength, or nucleophilicity, is a measure of how fast a Lewis base displaces a leaving group from a suitable substrate. By measuring the rate at which various Lewis bases react with methyl iodide in methanol, a list of their nucleophilicities relative to methanol as the standard nucleophile has been compiled. It is presented in Table 8.4 eutral Lewis bases such as water, alcohols, and carboxylic acids are much weaker nucleophiles than their conjugate bases. When comparing species that have the same nucleophilic atom, a negatively charged nucleophile is more reactive than a neutral one Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
8.7 NUCLEOPHILES AND NUCLEOPHILICITY The Lewis base that acts as the nucleophile often is, but need not always be, an anion. Neutral Lewis bases can also serve as nucleophiles. Common examples of substitutions involving neutral nucleophiles include solvolysis reactions. Solvolysis reactions are substitutions in which the nucleophile is the solvent in which the reaction is carried out. Solvolysis in water converts an alkyl halide to an alcohol. Solvolysis in methyl alcohol converts an alkyl halide to an alkyl methyl ether. In these and related solvolyses, the first stage is the one in which nucleophilic substitution takes place and is rate-determining. The proton-transfer step that follows it is much faster. Since, as we have seen, the nucleophile attacks the substrate in the ratedetermining step of the SN2 mechanism, it follows that the rate at which substitution occurs may vary from nucleophile to nucleophile. Just as some alkyl halides are more reactive than others, some nucleophiles are more reactive than others. Nucleophilic strength, or nucleophilicity, is a measure of how fast a Lewis base displaces a leaving group from a suitable substrate. By measuring the rate at which various Lewis bases react with methyl iodide in methanol, a list of their nucleophilicities relative to methanol as the standard nucleophile has been compiled. It is presented in Table 8.4. Neutral Lewis bases such as water, alcohols, and carboxylic acids are much weaker nucleophiles than their conjugate bases. When comparing species that have the same nucleophilic atom, a negatively charged nucleophile is more reactive than a neutral one. Methyl alcohol O H3C H Alkyl halide R X slow fast Dialkyloxonium halide O H3C H R X Alkyl methyl ether ROCH3 Hydrogen halide HX Water O H H Alkyl halide R X slow fast Alkyloxonium halide O H H R X Alcohol ROH Hydrogen halide HX 312 CHAPTER EIGHT Nucleophilic Substitution TABLE 8.3 Effect of Chain Branching on Reactivity of Primary Alkyl Bromides Toward Substitution Under SN2 Conditions* Alkyl bromide Ethyl bromide Propyl bromide Isobutyl bromide Neopentyl bromide CH3CH2Br CH3CH2CH2Br (CH3)2CHCH2Br (CH3)3CCH2Br Structure 1.0 0.8 0.036 0.00002 Relative rate† *Substitution of bromide by lithium iodide in acetone. † Ratio of second-order rate constant k for indicated alkyl bromide to k for ethyl bromide at 25°C. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
8.7 Nucleophiles and Nucleophilicity TABLE 8.4 Nucleophilicity of Some Common Nucleophiles Reactivity class Nucleophile Relative reactivity* Very good nucleophiles Good nucleophiles Br, Ho, RO,CN, N3 Fair nucleophiles NH3, CI, F, RCO Weak nucleophile H2O, ROH Very weak nucleophile RCoH Relative reactivity is nucleophile)k(methanol) for typical SN2 reactions and is approximate Data ethanol as the solvent RO is more nucleophilic than ROH RCO is more nucleophilic than RCOH Carboxy late ion As long as the nucleophilic atom is the same, the more basic the nucleophile, the more reactive it is. An alkoxide ion(Ro is more basic and more nucleophilic than a carboxylate ion(RCO 2) is more nucleophilic than RO Weaker base Conjugate acid is ROH: Conjugate acid is RCO2H e connection between basicity and nucleophilicity holds when comparing atoms in the same row of the periodic table. Thus, HO is more basic and more nucleophilic than F, and H3 N is more basic and more nucleophilic than H2O. It does not hold when proceeding down a column in the periodic table. For example, I is the least basic of the halide ions but is the most nucleophilic. F is the most basic halide ion but the least nucleophilic. The seems most responsible for the inverse relationship between basicity and nucleophilicity among the halide ions is the degree to which they are sol- vated by hydrogen bonds of the type illustrated in Figure 8.4. Smaller anions, because of their high charge-to-size ratio, are more strongly solvated than larger ones to act as a nucleophile, the halide must shed some of the solvent molecules that it. Among the halide anions, F forms the strongest hydrogen bonds to water and alco- hols, and I the weakest. Thus, the nucleophilicity of F is suppressed more than that of CI, Cl more than Br and Br more than I. Similarly, Ho is smaller, more sol vated, and less nucleophilic than HS Nucleophilicity is also related to polarizability, or the ease of distortion of the elec- A descriptive term applied to tron"cloud"surrounding the nucleophile. The partial bond between the nucleophile and a highly polarizable species the alkyl halide that characterizes the SN2 transition state is more fully developed at a longer distance when the nucleophile is very polarizable than when it is not. An increased nucleophile. Conversely degree of bonding to the nucleophile lowers the energy of the transition state and izable and is said to be hard nucleophile Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
8.7 Nucleophiles and Nucleophilicity 313 As long as the nucleophilic atom is the same, the more basic the nucleophile, the more reactive it is. An alkoxide ion (RO) is more basic and more nucleophilic than a carboxylate ion (RCO2 ). The connection between basicity and nucleophilicity holds when comparing atoms in the same row of the periodic table. Thus, HO is more basic and more nucleophilic than F, and H3N is more basic and more nucleophilic than H2O. It does not hold when proceeding down a column in the periodic table. For example, I is the least basic of the halide ions but is the most nucleophilic. F is the most basic halide ion but the least nucleophilic. The factor that seems most responsible for the inverse relationship between basicity and nucleophilicity among the halide ions is the degree to which they are solvated by hydrogen bonds of the type illustrated in Figure 8.4. Smaller anions, because of their high charge-to-size ratio, are more strongly solvated than larger ones. In order to act as a nucleophile, the halide must shed some of the solvent molecules that surround it. Among the halide anions, F forms the strongest hydrogen bonds to water and alcohols, and I the weakest. Thus, the nucleophilicity of F is suppressed more than that of Cl, Cl more than Br, and Br more than I. Similarly, HO is smaller, more solvated, and less nucleophilic than HS. Nucleophilicity is also related to polarizability, or the ease of distortion of the electron “cloud” surrounding the nucleophile. The partial bond between the nucleophile and the alkyl halide that characterizes the SN2 transition state is more fully developed at a longer distance when the nucleophile is very polarizable than when it is not. An increased degree of bonding to the nucleophile lowers the energy of the transition state and RO is more nucleophilic than Stronger base Conjugate acid is ROH: Ka 1016 (pKa 16) RCO O X Weaker base Conjugate acid is RCO2H: Ka 105 (pKa 5) RO is more nucleophilic than Alkoxide ion ROH Alcohol RCO is more nucleophilic than O X Carboxylate ion RCOH O X Carboxylic acid TABLE 8.4 Nucleophilicity of Some Common Nucleophiles Reactivity class Very good nucleophiles Good nucleophiles Fair nucleophiles Weak nucleophiles Very weak nucleophiles I , HS, RS Br, HO, RO, CN, N3 NH3, Cl, F, RCO2 H2O, ROH RCO2H Nucleophile 105 104 103 1 102 Relative reactivity* *Relative reactivity is k(nucleophile)/k(methanol) for typical SN2 reactions and is approximate. Data pertain to methanol as the solvent. A descriptive term applied to a highly polarizable species is soft. Iodide is a very soft nucleophile. Conversely, fluoride ion is not very polarizable and is said to be a hard nucleophile. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTER EIGHT Nucleophilic Substitution g RE 8.4 Solvation of a chloride by ion-dipole attractive forces with water. The negatively ned chloride ion interacts with the positively polarized hydrogens of water AN ENZYME-CATALYZED NUCLEOPHILIC SUBSTITUTION OF AN ALKYL HALIDE ucleophilic substitution is one of a variety of The product of this nucleophilic substitution then re- mechanisms by which living systems detoxify acts with water, restoring the enzyme to its original halogenated organic compounds introduced state and giving the observed products of the reac- into the environment. Enzymes that catalyze these tion. reactions are known as haloalkane dehalogenases The hydrolysis of 1, 2-dichloroethane to 2- several roethanol, for example, is a biological nucle ophilic substitution catalyzed by a dehalogenase CH2Cl dehalogenase CICH2 CH2CI+ 2H2O 1.2-Dichloroeth EnzymeFC-0: +HOCH2 +H3O CICH2 CH2OH+ CHCI 2-Chloroethanol Hydronium ion Chloride ion This stage of the reaction proceeds by a mechanism that will be discussed in Chapter 20. Both stages are The haloalkane dehydrogenase is believed to faster than the reaction of 1.2-dichloroethane with act by using one of its side-chain carboxylates to dis- water in the absence of the enzyme place chloride by an SN2 mechanism (Recall the reac- Some of the most common biological SN2 reac- tion of carboxylate ions with alkyl halides from Table tions involve attack at methyl groups, especially a methyl group of s-adenosylmethionine. Examples of these will be given in Chapter 16 Enzyme CHaCI CHCI Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
314 CHAPTER EIGHT Nucleophilic Substitution AN ENZYME-CATALYZED NUCLEOPHILIC SUBSTITUTION OF AN ALKYL HALIDE Nucleophilic substitution is one of a variety of mechanisms by which living systems detoxify halogenated organic compounds introduced into the environment. Enzymes that catalyze these reactions are known as haloalkane dehalogenases. The hydrolysis of 1,2-dichloroethane to 2- chloroethanol, for example, is a biological nucleophilic substitution catalyzed by a dehalogenase. The haloalkane dehydrogenase is believed to act by using one of its side-chain carboxylates to displace chloride by an SN2 mechanism. (Recall the reaction of carboxylate ions with alkyl halides from Table 8.1.) ±C±O O X SN2 Enzyme CH2±Cl CH2Cl W ±C±O±CH2 O X Enzyme CH2Cl W Cl ClCH2CH2Cl 1,2-Dichloroethane 2H2O Water ClCH2CH2OH 2-Chloroethanol H3O Hydronium ion Cl Chloride ion dehalogenase enzyme The product of this nucleophilic substitution then reacts with water, restoring the enzyme to its original state and giving the observed products of the reaction. This stage of the reaction proceeds by a mechanism that will be discussed in Chapter 20. Both stages are faster than the reaction of 1,2-dichloroethane with water in the absence of the enzyme. Some of the most common biological SN2 reactions involve attack at methyl groups, especially a methyl group of S-adenosylmethionine. Examples of these will be given in Chapter 16. ±C±O O X Enzyme HOCH2 CH2Cl W H3O several steps ±C±O±CH2 O X Enzyme CH2Cl W 2H2O Cl FIGURE 8.4 Solvation of a chloride by ion–dipole attractive forces with water. The negatively charged chloride ion interacts with the positively polarized hydrogens of water. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website