CHAPTER 8 NUCLEOPHILIC SUBSTITUTION hen we discussed elimination reactions in Chapter 5, we learned that a Lewis base can react with an alkyl halide to form an alkene. In the present chapter, you will find that the same kinds of reactants can also undergo a different reaction,one in which the Lewis base acts as a nucleophile to substitute for the halide substituent on carbon R-X:+Y R-Y +: X Alkyl Lewis base Product of Halide halid nucleophilic anion substitution We first encountered nucleophilic substitution in Chapter 4, in the reaction of alcohols with hydrogen halides to form alkyl halides. Now we'll see how alkyl halides can them- selves be converted to other classes of organic compounds by nucleophilic substitution This chapter has a mechanistic emphasis designed to achieve a practical result. By understanding the mechanisms by which alkyl halides undergo nucleophilic substitution, we can choose experimental conditions best suited to carrying out a particular functional group transformation. The difference between a successful reaction that leads cleanly to a desired product and one that fails is often a subtle one. Mechanistic analysis helps us to appreciate these subtleties and use them to our advantage 8.1 FUNCTIONAL GROUP TRANSFORMATION BY NUCLEOPHILIC SUBSTITUTION Nucleophilic substitution reactions of alkyl halides are related to elimination reactions n that the halogen acts as a leaving group on carbon and is lost as an anion. The car- bon-halogen bond of the alkyl halide is broken heterolytically: the pair of electrons in that bond are lost with the leaving group 302 Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
302 CHAPTER 8 NUCLEOPHILIC SUBSTITUTION When we discussed elimination reactions in Chapter 5, we learned that a Lewis base can react with an alkyl halide to form an alkene. In the present chapter, you will find that the same kinds of reactants can also undergo a different reaction, one in which the Lewis base acts as a nucleophile to substitute for the halide substituent on carbon. We first encountered nucleophilic substitution in Chapter 4, in the reaction of alcohols with hydrogen halides to form alkyl halides. Now we’ll see how alkyl halides can themselves be converted to other classes of organic compounds by nucleophilic substitution. This chapter has a mechanistic emphasis designed to achieve a practical result. By understanding the mechanisms by which alkyl halides undergo nucleophilic substitution, we can choose experimental conditions best suited to carrying out a particular functional group transformation. The difference between a successful reaction that leads cleanly to a desired product and one that fails is often a subtle one. Mechanistic analysis helps us to appreciate these subtleties and use them to our advantage. 8.1 FUNCTIONAL GROUP TRANSFORMATION BY NUCLEOPHILIC SUBSTITUTION Nucleophilic substitution reactions of alkyl halides are related to elimination reactions in that the halogen acts as a leaving group on carbon and is lost as an anion. The carbon–halogen bond of the alkyl halide is broken heterolytically: the pair of electrons in that bond are lost with the leaving group. Alkyl halide R X Lewis base Y Product of nucleophilic substitution R Y Halide anion X Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
8.1 Functional Group Transformation by Nucleophilic Substitution The carbon-halogen bond in an alkyl halide is polar R文 X=L. Br. CLF nd is cleaved on attack by a nucleophile so that the two electrons in the bond are retained R-Y+: X by the halogen The most frequently encountered nucleophiles in functional group transfo are anions, which are used as their lithium, sodium, or potassium salts. If we use M to represent lithium, sodium, or potassium, some representative nucleophilic reagents are MOR(a metal alkoxide, a source of the nucleophilic anion RO:) MOCr (a metal carboxylate, a source of the nucleophilic anion RC-O:) SH (a metal hydrogen sulfide, a source of the nucleophilic anion HS:) MCn(a metal cyanide, a source of the nucleophilic anion: CEN;) (a metal azide, a source of the nucleophilic anion: N=N=N:) Table8. 1 illustrates an application of each of these to a functional group transfor- mation. The anionic portion of the salt substitutes for the halogen of an alkyl halide. The netal cation portion becomes a lithium, sodium, or potassium halide. M+y:+r R-Y +M+:X Nucleophilic Alky Product of Metal halide halide nucleophilic substitution Notice that all the examples in Table 8. 1 involve alkyl halides, that is, compounds in which the halogen is attached to an sp-hybridized carbon. Alkenyl halides and aryl Alkenyl halides are also re- halides, compounds in which the halogen is attached to sp-hybridized carbons, are ferred to as vinylic halides essentially unreactive under these conditions, and the principles to be developed in this chapter do not apply to them sp-hybridized carbon sp-hybridized carbon Alkyl halide Alkenyl halide I halide To ensure that reaction occurs in homogeneous solution, solvents are chosen that dis solve both the alkyl halide and the ionic salt. The alkyl halide substrates 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 enough of both the substrate and the nucleophile to give fairly concentrated solutions are fre- The use of DMSO as a sok- quently used. Many salts, as well as most alkyl halides, posses cant solubility in vent in dehydrohalogenation eactions was mentioned dimethyl sulfoxide(DMsO), which makes this a good medium for carrying out nucle- earlier, in Section 5.14 Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
8.1 Functional Group Transformation by Nucleophilic Substitution 303 The most frequently encountered nucleophiles in functional group transformations are anions, which are used as their lithium, sodium, or potassium salts. If we use M to represent lithium, sodium, or potassium, some representative nucleophilic reagents are Table 8.1 illustrates an application of each of these to a functional group transformation. The anionic portion of the salt substitutes for the halogen of an alkyl halide. The metal cation portion becomes a lithium, sodium, or potassium halide. Notice that all the examples in Table 8.1 involve alkyl halides, that is, compounds in which the halogen is attached to an sp3 -hybridized carbon. Alkenyl halides and aryl halides, compounds in which the halogen is attached to sp2 -hybridized carbons, are essentially unreactive under these conditions, and the principles to be developed in this chapter do not apply to them. To ensure that reaction occurs in homogeneous solution, solvents are chosen that dissolve both the alkyl halide and the ionic salt. The alkyl halide substrates 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 enough of both the substrate and the nucleophile to give fairly concentrated solutions are frequently used. Many salts, as well as most alkyl halides, possess significant solubility in dimethyl sulfoxide (DMSO), which makes this a good medium for carrying out nucleophilic substitution reactions. sp2 sp -hybridized carbon 3 -hybridized carbon Alkyl halide C X Alkenyl halide X C C Aryl halide X Nucleophilic reagent M Y R X Alkyl halide R Y Product of nucleophilic substitution X M Metal halide MOR MOCR O X MSH MCN MN3 (a metal alkoxide, a source of the nucleophilic anion ) RO (a metal hydrogen sulfide, a source of the nucleophilic anion ) HS (a metal cyanide, a source of the nucleophilic anion ) CPN (a metal azide, a source of the nucleophilic anion NœNœN ) (a metal carboxylate, a source of the nucleophilic anion RC±O O X ) Y R X R Y X R X X I, Br, Cl, F The carbon–halogen bond in an alkyl halide is polar and is cleaved on attack by a nucleophile so that the two electrons in the bond are retained by the halogen Alkenyl halides are also referred to as vinylic halides. The use of DMSO as a solvent in dehydrohalogenation reactions was mentioned earlier, in Section 5.14. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTER EIGHT Nucleophilic Substitution TABLE 8.1 Representative Functional Group Transformations by Nucleophilic Substitution Nucleophile and comments General equation and specific example Alkoxide ion(RO: " )The oxygen atom of a metal alkoxide acts as a >ror+ nucleophile to replace the halogen of an alkyl halide. The product is Alkoxide ion Alkyl halide Ether Halide ion ether (CH3)2 ONa CH3 CH2Br (CH3)2CHCH2 OCH2 CH3+ NaBr Sodium Sodium bromide ether(66%) Carboxylate ion(RC-O: " ) An ester +1A义:一、o+ is formed when the negatively harged oxygen of a carboxylate Alkyl halide Ester Halide ion places the halogen of an alkyl KOC(CH2)16 CH3 CH3 CH2I 9 CH3CH2 OC(CH2) CH3 KI potassium Ethyl Potassium octadecanoate(95%) Hydrogen sulfide ion(HS: ")Use of ydrogen sulfide as a nucleophile ermits the conversion of alkyl hal- Hydrogen sulfide ion Alkyl halide Thiol Halide ion ides to compounds of the type RSH These compounds are the sulfur ana- KSH +CH3 CH(CH,) CH3 etnano CH3 CH(CH2)CH:+ KBr logs of alcohols and are known as 2-Nonanethiol nide ion is usually the Caim Te. e negativ C≡N p Cyanide ion Alkyl halide Alkyl cyanide Halide ion haracter. Use of cyanide ion as a nucleophile permits the extension of a carbon chain by carbon-carbon Nacn+ bond formation The product is an 0-a=D cn+ Nac alkyl cyanide, or nitrile. cyclo Sodium cya chloride chloride Azide ion(N=N=N: )Sodium azide N=N →RN=N=N:+ is a reagent used for carbon-nitro- gen bond formation the product is Azide ion Alkyl halide Alkyl azide Halide ion an alkyl azide 1-propanol- NaN3+ CH3(CH2)4I →CH(CH2)4N3+Nal Sodium Pentyl iodide Pentyl azide Sodium (52%) iodide Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
304 CHAPTER EIGHT Nucleophilic Substitution TABLE 8.1 Representative Functional Group Transformations by Nucleophilic Substitution Reactions of Alkyl Halides Nucleophile and comments Cyanide ion (:C PN:) The negatively charged carbon atom of cyanide ion is usually the site of its nucleophilic character. Use of cyanide ion as a nucleophile permits the extension of a carbon chain by carbon–carbon bond formation. The product is an alkyl cyanide, or nitrile. (Continued) Alkoxide ion (RO: ) The oxygen atom of a metal alkoxide acts as a nucleophile to replace the halogen of an alkyl halide. The product is an ether. : : Hydrogen sulfide ion (HS: ) Use of hydrogen sulfide as a nucleophile permits the conversion of alkyl halides to compounds of the type RSH. These compounds are the sulfur analogs of alcohols and are known as thiols. : : Azide ion (:N œN œN :) Sodium azide is a reagent used for carbon–nitrogen bond formation. The product is an alkyl azide. : : Carboxylate ion (RC±O: ) An ester is formed when the negatively charged oxygen of a carboxylate replaces the halogen of an alkyl halide. : : :O: X General equation and specific example Sodium isobutoxide (CH3)2CHCH2ONa Ethyl bromide CH3CH2Br Ethyl isobutyl ether (66%) (CH3)2CHCH2OCH2CH3 Sodium bromide NaBr isobutyl alcohol Potassium octadecanoate KOC(CH2)16CH3 O X Ethyl iodide CH3CH2I Ethyl octadecanoate (95%) CH3CH2OC(CH2)16CH3 O X Potassium iodide KI acetone water Pentyl iodide CH3(CH2)4I Sodium azide NaN3 Sodium iodide NaI Pentyl azide (52%) CH3(CH2)4N3 1-propanolwater Ether ROR Halide ion X Alkoxide ion RO Alkyl halide R X Halide ion X Alkyl halide R X Carboxylate ion RCO O X Ester RCOR O X Halide ion X Alkyl halide R X Hydrogen sulfide ion HS Thiol RSH Potassium hydrogen sulfide KSH 2-Bromononane CH3CH(CH2)6CH3 Br W 2-Nonanethiol (74%) CH3CH(CH2)6CH3 SH W Potassium bromide KBr ethanol water Halide ion X Alkyl halide R X Cyanide ion NPC Alkyl cyanide RCPN Halide ion X Alkyl halide R X Alkyl azide RNœNœN Azide ion NœNœN Sodium cyanide NaCN Cl Cyclopentyl chloride CN Cyclopentyl cyanide (70%) Sodium chloride NaCl DMSO Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
8.2 Relative Reactivity of Halide Leaving Groups TABLE 8.1 Representative Functional Group Transformations by Nucleophilic Substitution Reactions of Alkyl Halides(Continued) Nucleophile and comments General equation and specific example lodide ion (:: )Alkyl chlorides and bromides are converted to alkyl dide in acetone. Nal is soluble in lodide ion Alkyl chloride Alkyl iodide Chloride or acetone, but NaCl and NaBr are bromide io soluble and crystallize from the reaction mixture, driving the reac- CH3 CHCH3 CH3CHCH3 NaBr (solid) tion to complet 2-Bromopropane Sodium 2-lodopropand 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 (a)NaOH (sodium hydroxide (b)KOCH2 CH3(potassium ethoxide NaoC (sodium benzoate) (d)LiN3(lithium azide) (e)KCN (potassium cyanide NaSH (sodium hydrogen sulfid (g)Nal (sodium iodide) SAMPLE SOLUTION (a)The nucleophile in sodium hydroxide is the negatively charged hydroxide ion. The reaction that occurs is nucleophilic substitution of bro- mide by hydroxide. the product is methyl alcohol CH3--Br CH3OH+ Hydroxide ion Methyl bromide Methyl alcohol Bromide ion (substrate) product) (leaving group) With this as background, you can begin to see how useful alkyl halides are in syn- thetic organic chemistry. Alkyl halides may be prepared from alcohols by nucleophilic substitution, from alkanes by free-radical halogenation, and from alkenes by addition of hydrogen halides. They then become available as starting materials for the preparation of other functionally substituted organic compounds by replacement of the halide leav ing group with a nucleophile. The range of compounds that can be prepared by nucle- ophilic substitution reactions of alkyl halides is quite large; the examples shown in Table 8. 1 illustrate only a few of them. Numerous other examples will be added to the list in is and subsequent chapters 8.2 RELATIVE REACTIVITY OF HALIDE LEAVING GROUPS Among alkyl halides, alkyl iodides undergo nucleophilic substitution at the fastest rate, alkyl fluorides the slowest. Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
8.2 Relative Reactivity of Halide Leaving Groups 305 TABLE 8.1 Representative Functional Group Transformations by Nucleophilic Substitution Reactions of Alkyl Halides (Continued) Nucleophile and comments Iodide ion (:I: ) Alkyl chlorides and bromides are converted to alkyl iodides by treatment with sodium iodide in acetone. NaI is soluble in acetone, but NaCl and NaBr are insoluble and crystallize from the reaction mixture, driving the reaction to completion. : : General equation and specific example 2-Bromopropane CH3CHCH3 W Br Sodium iodide NaI 2-Iodopropane (63%) CH3CHCH3 I W Sodium bromide NaBr (solid) acetone Chloride or bromide ion X Iodide ion I Alkyl chloride or bromide R X Alkyl iodide R I acetone 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: (a) NaOH (sodium hydroxide) (b) KOCH2CH3 (potassium ethoxide) (c) (d) LiN3 (lithium azide) (e) KCN (potassium cyanide) (f) NaSH (sodium hydrogen sulfide) (g) NaI (sodium iodide) 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. With this as background, you can begin to see how useful alkyl halides are in synthetic organic chemistry. Alkyl halides may be prepared from alcohols by nucleophilic substitution, from alkanes by free-radical halogenation, and from alkenes by addition of hydrogen halides. They then become available as starting materials for the preparation of other functionally substituted organic compounds by replacement of the halide leaving group with a nucleophile. The range of compounds that can be prepared by nucleophilic substitution reactions of alkyl halides is quite large; the examples shown in Table 8.1 illustrate only a few of them. Numerous other examples will be added to the list in this and subsequent chapters. 8.2 RELATIVE REACTIVITY OF HALIDE LEAVING GROUPS Among alkyl halides, alkyl iodides undergo nucleophilic substitution at the fastest rate, alkyl fluorides the slowest. Hydroxide ion (nucleophile) HO Methyl bromide (substrate) CH3 Br Bromide ion (leaving group) Br Methyl alcohol (product) CH3 OH NaOC O (sodium benzoate) Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTER EIGHT Nucleophilic Substitution Increasing rate of substitution RF RCI RB Least reactive Most reactive The order of alkyl halide reactivity in nucleophilic substitutions is the same as their order in eliminations. lodine has the weakest bond to carbon and iodide is the best leavin 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 car bon, and fluoride is the poorest leaving group. Alkyl fluorides are rarely used as sub- strates in nucleophilic substitution because they are several thousand times less reactive han alkyl chlorides propane was allowed to react with one molar equivalent of sodium cyanide:o. PROBLEM 8.2 A single organic product was obtained when 1-bromo-3-chlor aqueous ethanol. What was this product? Leaving-group ability is also related to basicity. A strongly basic anion is usually aving group ability and ba. a poorer leaving group than a weakly basic one. Fluoride is the most basic and the poor sicity is explored in more de. est leaving group among the halide anions, iodide the least basic and the best leav 8.3 THE SN2 MECHANISM OF NUCLEOPHILIC SUBSTITUTION The mechanisms by which nucleophilic substitution takes place have been the subject of much study. Extensive research by Sir Christopher Ingold and Edward D. Hughes and their associates at University College, London, during the 1930s emphasized kinetic and eochemical measurements to probe the te mechanisms of these reactions Recall that the term kinetics" refers to how the rate of a reaction varies wi changes in concentration. Consider the nucleophilic substitution in which sodium hydrox ide reacts with methyl bromide to form methyl alcohol and sodium bromide →>CH3OH+Br Methyl bromide Hydroxide ion Methyl alcohol Bromide ion The rate of this reaction is observed to be directly proportional to the concentration of both methyl bromide and sodium hydroxide. It is first-order in each reactant, or second Rate= k[Ch3 Br[HO I Hughes and Ingold interpreted second-order kinetic behavior to mean that the rate determining step is bimolecular that is, that both hydroxide ion and methyl bromide involved at the transition state. The symbol given to the detailed description of the mech- The Sn2 mechanism was in anism that they developed is SN2, standing for substitution nucleophilic bimolecular. The Hughes and Ingold SN2 mechanism is a single-step process in which both the 4.13 alkyl halide and the nucleophile are involved at the transition state. Cleavage of the bond between carbon and the leaving group is assisted by formation of a bond between car bon and the nucleophile. In effect, the nucleophile "pushes off" the leaving group from Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
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. PROBLEM 8.2 A single organic product was obtained when 1-bromo-3-chloropropane was allowed to react with one molar equivalent of sodium cyanide in aqueous ethanol. What was this product? Leaving-group ability is also related to basicity. A strongly basic anion is usually a poorer leaving group than a weakly basic one. Fluoride is the most basic and the poorest leaving group among the halide anions, iodide the least basic and the best leaving group. 8.3 THE SN2 MECHANISM OF NUCLEOPHILIC SUBSTITUTION The mechanisms by which nucleophilic substitution takes place have been the subject of much study. Extensive research by Sir Christopher Ingold and Edward D. Hughes and their associates at University College, London, during the 1930s emphasized kinetic and stereochemical measurements to probe the mechanisms of these reactions. Recall that the term “kinetics” refers to how the rate of a reaction varies with changes in concentration. Consider the nucleophilic substitution in which sodium hydroxide reacts with methyl bromide to form methyl alcohol and sodium bromide: The rate of this reaction is observed to be directly proportional to the concentration of both methyl bromide and sodium hydroxide. It is first-order in each reactant, or secondorder overall. Rate k[CH3Br][HO] Hughes and Ingold interpreted second-order kinetic behavior to mean that the ratedetermining step is bimolecular, that is, that both hydroxide ion and methyl bromide are involved at the transition state. The symbol given to the detailed description of the mechanism that they developed is SN2, standing for substitution nucleophilic bimolecular. The Hughes and Ingold SN2 mechanism is a single-step process in which both the alkyl halide and the nucleophile are involved at the transition state. Cleavage of the bond between carbon and the leaving group is assisted by formation of a bond between carbon and the nucleophile. In effect, the nucleophile “pushes off” the leaving group from Methyl bromide CH3Br Hydroxide ion HO Bromide ion Br Methyl alcohol CH3OH Increasing rate of substitution by nucleophiles RF RCl RBr RI Least reactive Most reactive 306 CHAPTER EIGHT Nucleophilic Substitution The relationship between leaving group ability and basicity is explored in more detail in Section 8.14. The SN2 mechanism was introduced earlier in Section 4.13. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website