《有机化学》课程教学资源（教材文献，英文版）CHAPTER 8 NUCLEOPHILIC SUBSTITUTION.pdf_大学文库

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

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

8.4 Stereochemistry of SN2 Reactions ts point of attachment to carbon. For this reason, the SN2 mechanism is sometimes referred to as a direct displacement process. The SN2 mechanism for the hydrolysis of methyl bromide may be represented by a single elementary step HO: t CH3 Br HO---CH3---Br:-HOCH3 : Br Hydroxide Methyl Transition Methyl Carbon is partially bonded to both the incoming nucleophile and the departing halide at the transition state. Progress is made toward the transition state as the nucleophile begins to share a pair of its electrons with carbon and the halide ion leaves, taking with it the pair of electrons in its bond to carbon PROBLEM 8.3 Is the two-step sequence depicted in the following equations con- sistent with the second-order kinetic behavior observed for the hydrolysis of methyl bromide? CH3+ HO CH3OH The SN2 mechanism is believed to describe most substitutions in which simple pri mary and secondary alkyl halides react with anionic nucleophiles. All the examples cited in Table 8. 1 proceed by the Sn2 mechanism (or a mechanism very much like SN2- remember, mechanisms can never be established with certainty but represent only our best present explanations of experimental observations). We'll examine the SN2 mecha- nism, particularly the structure of the transition state, in more detail in Section 8.5 after first looking at some stereochemical studies carried out by Hughes and Ingold. 8.4 STEREOCHEMISTRY OF SN2 REACTIONS What is the structure of the transition state in an SN2 reaction? In particular, what is the spatial arrangement of the nucleophile in relation to the leaving group as reactants pass through the transition state on their way to products? Two stereochemical possibilities present themselves. In the pathway shown in Fig ure &la, the nucleophile simply assumes the position occupied by the leaving group. It attacks the substrate at the same face from which the leaving group departs. This is called front-side displacement, or substitution with retention of configuration In a second possibility, illustrated in Figure 8.1b, the nucleophile attacks the sub strate from the side opposite the bond to the leaving group. This is called"back-side dis placement, "or substitution with inversion of configuration. Which of these two opposite stereochemical possibilities operates was determined in experiments with optically active alkyl halides. In one such experiment, Hughes and Ingold determined that the reaction of 2-bromooctane with hydroxide ion gave 2-octanol having a configuration opposite that of the starting alkyl halid ample have opposite config. CH3(CH,)5 (CH2)5CH3 NaOH opposite signs of rotation, it →>HO CH halide/alcohol pairs. (See Sec. tion 7.5) (S)-(+)-2-Bromooctane (R)-(-)-2-Octanol Back Forward Main MenuToc Study Guide ToC Student o MHHE Website

8.4 Stereochemistry of SN2 Reactions 307 its point of attachment to carbon. For this reason, the SN2 mechanism is sometimes referred to as a direct displacement process. The SN2 mechanism for the hydrolysis of methyl bromide may be represented by a single elementary step: Carbon is partially bonded to both the incoming nucleophile and the departing halide at the transition state. Progress is made toward the transition state as the nucleophile begins to share a pair of its electrons with carbon and the halide ion leaves, taking with it the pair of electrons in its bond to carbon. PROBLEM 8.3 Is the two-step sequence depicted in the following equations consistent with the second-order kinetic behavior observed for the hydrolysis of methyl bromide? The SN2 mechanism is believed to describe most substitutions in which simple primary and secondary alkyl halides react with anionic nucleophiles. All the examples cited in Table 8.1 proceed by the SN2 mechanism (or a mechanism very much like SN2— remember, mechanisms can never be established with certainty but represent only our best present explanations of experimental observations). We’ll examine the SN2 mechanism, particularly the structure of the transition state, in more detail in Section 8.5 after first looking at some stereochemical studies carried out by Hughes and Ingold. 8.4 STEREOCHEMISTRY OF SN2 REACTIONS What is the structure of the transition state in an SN2 reaction? In particular, what is the spatial arrangement of the nucleophile in relation to the leaving group as reactants pass through the transition state on their way to products? Two stereochemical possibilities present themselves. In the pathway shown in Figure 8.1a, the nucleophile simply assumes the position occupied by the leaving group. It attacks the substrate at the same face from which the leaving group departs. This is called “front-side displacement,” or substitution with retention of configuration. In a second possibility, illustrated in Figure 8.1b, the nucleophile attacks the substrate from the side opposite the bond to the leaving group. This is called “back-side displacement,” or substitution with inversion of configuration. Which of these two opposite stereochemical possibilities operates was determined in experiments with optically active alkyl halides. In one such experiment, Hughes and Ingold determined that the reaction of 2-bromooctane with hydroxide ion gave 2-octanol having a configuration opposite that of the starting alkyl halide. (S)-()-2-Bromooctane C H H3C CH3(CH2)5 Br (R)-()-2-Octanol H CH3 (CH2)5CH3 HO C NaOH ethanol-water CH3Br CH3 Br slow CH3 HO CH3OH fast Hydroxide ion HO Methyl bromide CH3Br Transition state HO CH3 Br Bromide ion Br Methyl alcohol HOCH3 Although the alkyl halide and alcohol given in this example have opposite configurations when they have opposite signs of rotation, it cannot be assumed that this will be true for all alkyl halide/alcohol pairs. (See Section 7.5) Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website

CHAPTER EIGHT Nucleophilic Substitution FIGURE 8.1 Two contrasting ubstitution of a leaving group(red) by a nucleophile blue). In(a)the nucleophile attacks carbon at the same side from which the leaving group departs In(b)nucle ophilic attack occurs at the (a) Nucleophilic substitution with retention of configuration side opposite the bond to the leaving group. (b)Nucleophilic substitution with inversion of configuration Nucleophilic substitution had occurred with inversion of configuration, consistent with the following transition state CH3(CH,)s H HO PROBLEM 8.4 The Fischer projection formula for (+)-2-bromooctane is shown For a ch Write the Fischer projection of the (-)-2-octanol formed from it by nucleophilic with molecu. substitution with inversion of configuration structura H CH2( CH2)4CH3 PROBLEM 8.5 Would you expect the 2-octanol formed by sn2 hydrolysis of (-) tion and sign of rotation? What about the 2-octanol formed by hydrolysis of racemic 2-brom Numerous similar experiments have demonstrated the generality of this observation. Substitution by the SN2 mechanism is stereospecific and proceeds with inversion of con The first example of a stereo. figuration at the carbon that bears the leaving group. There is a stereoelectronic require- electronic effect in this text ment for the nucleophile to approach carbon from the side opposite the bond to the leav. concerned anti elimination ing group. Organic chemists often speak of this as a Walden inversion, after the German E2 reactions of alkyl halides(Section 5. 16) heist Paul Walden, who described the earliest experiments in this area in the 1890 8.5 HOW SN2 REACTIONS OCCUR When we consider the overall reaction stereochemistry along with the kinetic data, a fairly complete picture of the bonding changes that take place during SN2 reactions merges. The potential energy diagram of Figure 8.2 for the hydrolysis of (S)-(+)-2- ctane is one that is consistent with the experimental observations Back Forward Main MenuToc Study Guide ToC Student o MHHE Website

Nucleophilic substitution had occurred with inversion of configuration, consistent with the following transition state: PROBLEM 8.4 The Fischer projection formula for ()-2-bromooctane is shown. Write the Fischer projection of the ()-2-octanol formed from it by nucleophilic substitution with inversion of configuration. PROBLEM 8.5 Would you expect the 2-octanol formed by SN2 hydrolysis of ()- 2-bromooctane to be optically active? If so, what will be its absolute configuration and sign of rotation? What about the 2-octanol formed by hydrolysis of racemic 2-bromooctane? Numerous similar experiments have demonstrated the generality of this observation. Substitution by the SN2 mechanism is stereospecific and proceeds with inversion of con- figuration at the carbon that bears the leaving group. There is a stereoelectronic requirement for the nucleophile to approach carbon from the side opposite the bond to the leaving group. Organic chemists often speak of this as a Walden inversion, after the German chemist Paul Walden, who described the earliest experiments in this area in the 1890s. 8.5 HOW SN2 REACTIONS OCCUR When we consider the overall reaction stereochemistry along with the kinetic data, a fairly complete picture of the bonding changes that take place during SN2 reactions emerges. The potential energy diagram of Figure 8.2 for the hydrolysis of (S)-()-2- bromooctane is one that is consistent with the experimental observations. CH3 H Br CH2(CH2)4CH3 C CH3(CH2)5 H HO Br CH3 308 CHAPTER EIGHT Nucleophilic Substitution (a) Nucleophilic substitution with retention of configuration (b) Nucleophilic substitution with inversion of configuration The first example of a stereoelectronic effect in this text concerned anti elimination in E2 reactions of alkyl halides (Section 5.16). For a change of pace, try doing Problem 8.4 with molecular models instead of making structural drawings. FIGURE 8.1 Two contrasting stereochemical pathways for substitution of a leaving group (red) by a nucleophile (blue). In (a) the nucleophile attacks carbon at the same side from which the leaving group departs. In (b) nucleophilic attack occurs at the side opposite the bond to the leaving group. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website

8.5 How SN2 Reactions Occur 309 Hydroxide ion acts as a nucleophile, using an unshared electron pair to attack carbon from the side opposite the bond to the leaving group. The hybridization of the carbon at which substitution occurs changes from sp3 in the alkyl halide to sp2 in the transition state. Both the nucleophile (hydroxide) and the leaving group (bromide) are partially bonded to this carbon in the transition state. We say that the SN2 transition state is pentacoordinate; carbon is fully bonded to three substituents and partially bonded to both the leaving group and the incoming nucleophile. The bonds to the nucleophile and the leaving group are relatively long and weak at the transition state. Once past the transition state, the leaving group is expelled and carbon becomes tetracoordinate, its hybridization returning to sp3 . During the passage of starting materials to products, three interdependent and synchronous changes take place: 1. Stretching, then breaking, of the bond to the leaving group 2. Formation of a bond to the nucleophile from the opposite side of the bond that is broken 3. Stereochemical inversion of the tetrahedral arrangement of bonds to the carbon at which substitution occurs Although this mechanistic picture developed from experiments involving optically active alkyl halides, chemists speak even of methyl bromide as undergoing nucleophilic substitution with inversion. By this they mean that tetrahedral inversion of the bonds to carbon occurs as the reactant proceeds to the product. Hydroxide ion HO Methyl bromide C H H H Br Transition state HO C Br H H H Bromide ion Br Methyl alcohol H H H HO C Potential energy Pentacoordinate carbon is sp2 - hybridized Bonding is weak between carbon and bromine and carbon and oxygen in the transition state Reaction coordinate CH3 (CH2)5 CH3 (CH2)5 CH3 CH3 CH3 Br (CH2)5 CH3 Br H H H C C HO C HO Br HO C(sp O bond σ 3 ) C(sp Br bond σ 3 ) δ δ FIGURE 8.2 Hybrid orbital description of the bonding changes that take place at carbon during nucleophilic substitution by the SN2 mechanism. For an animation of this SN2 reaction, see Learning By Modeling. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website

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 Website

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 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 hydrogens 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 hydrogen 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

8.6 Steric Effects in SN2 Reactions 311 PROBLEM 8.6 Identify the compound in each of the following pairs that reacts with sodium iodide in acetone at the faster rate: (a) 1-Chlorohexane or cyclohexyl chloride (b) 1-Bromopentane or 3-bromopentane (c) 2-Chloropentane or 2-fluoropentane (d) 2-Bromo-2-methylhexane or 2-bromo-5-methylhexane (e) 2-Bromopropane or 1-bromodecane SAMPLE SOLUTION (a) Compare the structures of the two chlorides. 1-Chlorohexane is a primary alkyl chloride; cyclohexyl chloride is secondary. Primary alkyl halides are less crowded at the site of substitution than secondary ones and react faster in substitution by the SN2 mechanism. 1-Chlorohexane is more reactive. Alkyl groups at the carbon atom adjacent to the point of nucleophilic attack also decrease the rate of the SN2 reaction. Compare the rates of nucleophilic substitution in the series of primary alkyl bromides shown in Table 8.3. Taking ethyl bromide as the standard and successively replacing its C-2 hydrogens by methyl groups, we see that each additional methyl group decreases the rate of displacement of bromide by iodide. The effect is slightly smaller than for alkyl groups that are attached directly to the carbon that bears the leaving group, but it is still substantial. When C-2 is completely substituted by methyl groups, as it is in neopentyl bromide [(CH3)3CCH2Br], we see the unusual case of a primary alkyl halide that is practically inert to substitution by the SN2 mechanism because of steric hindrance. Cyclohexyl chloride (secondary, less reactive) H Cl 1-Chlorohexane (primary, more reactive) CH3CH2CH2CH2CH2CH2Cl Least crowded– most reactive Most crowded– least reactive CH3Br CH3CH2Br (CH3)2CHBr (CH3)3CBr FIGURE 8.3 Ball-and-spoke and space-filling models of alkyl bromides, showing how substituents shield the carbon atom that bears the leaving group from attack by a nucleophile. The nucleophile must attack from the side opposite the bond to the leaving group. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website