Nucleophilic Substitution

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1 8 CAPTER UTLINE 8.1 Functional Group Transformation by Nucleophilic Substitution Relative Reactivity of alide Leaving Groups The S N 2 Mechanism of Nucleophilic Substitution Steric Effects and S N 2 Reaction Rates Nucleophiles and Nucleophilicity 315 Enzyme-Catalyzed Nucleophilic Substitutions of Alkyl alides The S N 1 Mechanism of Nucleophilic Substitution Stereochemistry of S N 1 Reactions Carbocation Rearrangements in S N 1 Reactions Effect of Solvent on the Rate of Nucleophilic Substitution Substitution and Elimination as Competing Reactions Nucleophilic Substitution of Alkyl Sulfonates Nucleophilic Substitution and Retrosynthetic Analysis Summary 333 Problems 335 Descriptive Passage and Interpretive Problems 8: Nucleophilic Substitution 340 This electrostatic potential map is of the transition state for the reaction of hydroxide ion with chloromethane. The tetrahedral arrangement of bonds inverts like an umbrella in a storm during the reaction. Nucleophilic Substitution W 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 halogen substituent on carbon. R X Alkyl halide Y Lewis base R Y Product of nucleophilic substitution X alide anion 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. 306

2 8.1 Functional Group Transformation by Nucleophilic Substitution 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 two electrons in that bond are lost with the leaving group. 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 R X X I,,, F Y R X R Y X The most frequently encountered nucleophiles 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 MR X MCR MS MCN MN 3 (a metal alkoxide, a source of the nucleophilic anion R ) X (a metal carboxylate, a source of the nucleophilic anion RC± ) (a metal hydrogen sulfide, a source of the nucleophilic anion S ) (a metal cyanide, a source of the nucleophilic anion CPN ) (a metal azide, a source of the nucleophilic anion NœNœN ) 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. M Y R X R Y M X Nucleophilic reagent Alkyl halide Product of nucleophilic substitution Metal halide Notice that all the examples in Table 8.1 involve alkyl halides, that is, compounds in which the halogen is attached to an sp 3 -hybridized carbon. Alkenyl halides and aryl halides, compounds in which the halogen is attached to sp 2 -hybridized carbons, are essentially Alkenyl halides are also referred to as vinylic halides. TABLE 8.1 Functional Group Transformation via Nucleophilic Substitution Nucleophile and comments Alkoxide ion: The oxygen atom of a metal alkoxide is nucleophilic and replaces the halogen of an alkyl halide. The product is an ether. General equation and specific example R R' X RR' X Alkoxide ion Alkyl halide Ether alide ion Na isobutyl alcohol Sodium isobutoxide Ethyl bromide Ethyl isobutyl ether (66%) Continued

3 308 Chapter 8 Nucleophilic Substitution TABLE 8.1 Functional Group Transformation via Nucleophilic Substitution (Continued ) Nucleophile and comments General equation and specific example Carboxylate ion: An ester is formed when the negatively charged oxygen of a carboxylate replaces the halogen of an alkyl halide. RC R' X RCR' X Carboxylate ion Alkyl halide Ester alide ion C 3 (C 2 ) 16 CK Potassium octadecanoate C 3 C 2 I acetone water C 3 (C 2 ) 16 CC 2 C 3 Ethyl iodide Ethyl octadecanoate (95%) ydrogen sulfide ion: Using hydrogen sulfide as a nucleophile permits the conversion of alkyl halides to thiols. S ydrogen sulfide ion R' X SR' X Alkyl halide Thiol alide ion KS C 3 C(C 2 ) 6 C 3 Potassium hydrogen sulfide ethanol water C 3 C(C 2 ) 6 C 3 S 2-omononane 2-Nonanethiol (74%) Cyanide ion: The negatively charged carbon of cyanide is the site of its nucleophilic character. Cyanide reacts with alkyl halides to extend a carbon chain by forming an alkyl cyanide or nitrile. N C R' X N CR' X Cyanide ion Alkyl halide Alkyl cyanide alide ion NaCN dimethyl sulfoxide CN Sodium cyanide Cyclopentyl chloride Cyclopentyl cyanide (70%) Azide ion: Sodium azide makes carbon-nitrogen bonds by converting an alkyl halide to an alkyl azide. N N N R' X N N NR' X Azide ion Alkyl halide Alkyl azide alide ion 1-propanol NaN 3 I water N 3 Sodium azide Pentyl iodide Pentyl azide (52%) Iodide ion: Alkyl chlorides and bromides are converted to alkyl iodides by treatment with sodium iodide in acetone. NaI is soluble in acetone, but the Na or Na that is formed is not and crystallizes from the reaction mixture, making the reaction irreversible. I R' X IR' X Iodide ion NaI Sodium iodide Alkyl chloride or bromide Alkyl iodide acetone Chloride or bromide ion I 2-omopropane 2-Iodopropane (63%)

4 8.2 Relative Reactivity of alide Leaving Groups 309 unreactive under these conditions, and the principles to be developed in this chapter do not apply to them. sp 3 -hybridized carbon sp 2 -hybridized carbon C X Alkyl halide C C X Alkenyl halide X Aryl halide 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 significant solubility in dimethyl sulfoxide (DMS) or N, N-dimethylformamide (DMF), which makes them good solvents for carrying out nucleophilic substitution reactions (Section 8.9). The use of DMS as a solvent in elimination reactions was mentioned earlier, in Section 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) Na (sodium hydroxide) (d) LiN 3 (lithium azide) (b) KC 2 C 3 (potassium ethoxide) (e) KCN (potassium cyanide) (c) (f) NaS (sodium hydrogen sulfide) NaC (sodium benzoate) (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. 3 C 3 C ydroxide ion (nucleophile) Methyl bromide (substrate) Methyl alcohol (product) omide ion (leaving group) With Table 8.1 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 alide Leaving Groups Among alkyl halides, alkyl iodides undergo nucleophilic substitution at the fastest rate, alkyl fluorides the slowest. Increasing rate of substitution by nucleophiles RF R R RI Least reactive Most reactive

5 310 Chapter 8 Nucleophilic Substitution Alkyl iodides are several times more reactive than alkyl bromides and from 50 to 100 times more reactive than alkyl chlorides. Alkyl fluorides are several thousand times less reactive than alkyl chlorides and are rarely used in nucleophilic substitutions. These reactivity differences can be related to the (1) the carbon halogen bond strength and (2) the basicity of the halide anion. Alkyl iodides have the weakest carbon halogen bond and require the lowest activation energy to break; alkyl fluorides have the strongest carbon halogen bond and require the highest activation energy. Regarding basicity of the halide leaving group, iodide is the weakest base, fluoride the strongest. It is generally true that the less basic the leaving group, the smaller the energy requirement for cleaving its bond to carbon and the faster the rate. The relationship between leaving-group ability and basicity is explored in more detail in Section 8.11 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? 8.3 The S N 2 Mechanism of Nucleophilic Substitution At about the same time as his studies of the mechanisms of elimination reactions, Sir Christopher Ingold and his collaborator Edward D. ughes applied the tools of kinetics and stereochemistry to nucleophilic substitution. Kinetics: aving already seen that the rate of nucleophilic substitution depends on the leaving group (I > > > F), we know that the carbon halogen bond must break in the slow step of the reaction and, therefore, expect the concentration of the alkyl halide to appear in the rate law. What about the nucleophile? ughes and Ingold found that many nucleophilic substitutions, such as the hydrolysis of methyl bromide in base: C 3 C 3 The S N 2 mechanism was introduced earlier in Section Methyl bromide ydroxide ion Methyl alcohol omide ion obey a second-order rate law, first order in the alkyl halide and first order in the nucleophile. Rate = k[c 3 ][ ] The most reasonable conclusion is that both hydroxide ion and methyl bromide react together in a bimolecular elementary step and that this step is rate-determining. The mechanism proposed by ughes and Ingold, called by them substitution nucleophilic bimolecular (S N 2) is shown as an equation in Mechanism 8.1 and as a potential energy diagram in Figure 8.1. It is a one-step concerted process in which both the alkyl halide and the nucleophile are involved at the transition state. eavage 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 its point of attachment to carbon. 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? 3 C slow C 3 C fast 3 C 3

6 8.3 The SN2 S N 2 Mechanism of Nucleophilic Substitution 311 Mechanism 8.1 The S N 2 Mechanism of Nucleophilic Substitution TE VERALL REACTIN: C 3 ± C 3 Methyl bromide ydroxide ion Methyl alcohol omide ion TE MECANISM: The reaction proceeds in a single step. ydroxide ion acts as a nucleophile. While the C bond is breaking, the C bond is forming. 3 C ± C 3 ydroxide ion Methyl bromide Methyl alcohol omide ion TE TRANSITIN STATE: ydroxide ion attacks carbon from the side opposite the C bond.,, C,, A $ Carbon is partially bonded to both hydroxide and bromide. The arrangement of bonds undergoes tetrahedral inversion from C to C as the reaction progresses.,,, C,, A $ Figure 8.1 Potential energy diagram for the reaction of methyl bromide with hydroxide ion by the S N 2 mechanism. Potential energy [ C A C [ A Reaction coordinate Stereochemistry. The diagram for the transition state in Mechanism 8.1 and Figure 8.1 for the reaction of methyl bromide with hydroxide anticipates a key stereochemical feature of the S N 2 mechanism. The nucleophile attacks carbon from the side opposite the bond to the leaving group. Another way of expressing the same point, especially when substitution occurs at a chirality center, is that S N 2 reactions proceed with inversion of configuration at

7 312 Chapter 8 Nucleophilic Substitution the carbon that bears the leaving group. The tetrahedral arrangement of bonds in the reactant is converted to an inverted tetrahedral arrangement in the product. S S Nucleophile Alkyl halide S N 2 product Leaving group 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. This stereochemical fact comes from studies of nucleophilic substitutions of optically active alkyl halides. In one such experiment, ughes and Ingold determined that the reaction of optically active 2-bromooctane with hydroxide ion gave 2-octanol, having the opposite configuration at its chirality center. S-()-2-omooctane Na ethanol water R-( )-2-ctanol Nucleophilic substitution had occurred with inversion of configuration, consistent with the following transition state: C 3 (C 2 ) 5,, C,, Problem 8.4 The Fischer projection for ()-2-bromooctane is shown. Write the Fischer projection of the ( )-2-octanol formed from it by the S N 2 mechanism. C 3 $ A C 3 C 2 (C 2 ) 4 C 3 Problem 8.5 Would you expect the 2-octanol formed by S N 2 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? The first example of a stereoelectronic effect in this text concerned anti elimination in E2 reactions of alkyl halides (Section 5.16). Countless experiments have confirmed that substitution by the S N 2 mechanism is stereospecific and suggests that there exists a stereoelectronic requirement for the nucleophile to approach carbon from the side opposite the bond to the leaving group. The results of molecular orbital calculations help us understand why. When a nucleophile such as hydroxide ion reacts with methyl bromide, electrons flow from the highest occupied molecular orbital (M) of to the lowest unoccupied molecular orbital (LUM) of C 3. Directing our attention to the LUM of C 3, we find three main regions where the M of the nucleophile can overlap with the LUM. ne of these the blue region shown at the right can be ignored because it is associated only with, and nucleophilic attack from that direction does not produce a C bond.

8 8.4 Steric Effects and SN2 S N Reaction Rates 313 Node Nucleophile attacks here C LUM of methyl bromide The region between carbon and bromine contains a nodal surface; therefore, no net bonding results from its overlap with the M of. The remaining possibility, which is also the one that coincides with experimental observation, is overlap of the M of with the LUM of C 3 in the region opposite the C bond. It involves a major region of the LUM, avoids a node, and gives a C bond with inversion of configuration at carbon. The S N 2 mechanism is believed to describe most substitutions in which simple primary and secondary alkyl halides react with negatively charged nucleophiles. All the examples that introduced nucleophilic substitution in Table 8.1 proceed by the S N 2 mechanism (or a mechanism very much like S N 2 remember, mechanisms can never be established with certainty but represent only our best present explanations of experimental observations). Problem 8.6 Sketch the structure of the S N 2 transition state for the following reaction taken from Table 8.1. Na is a spectator ion and can be omitted from the transition state. acetone (C 3 ) 2 C NaI (C 3 ) 2 CI Na 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 larger effect. 8.4 Steric Effects and S N 2 Reaction Rates There are very large differences in the rates at which the various kinds of alkyl halides methyl, primary, secondary, or tertiary undergo nucleophilic substitution. For the reaction: R LiI acetone Alkyl bromide Lithium iodide RI Li Alkyl iodide Lithium bromide the rates of nucleophilic substitution of a series of alkyl bromides differ by a factor of over Increasing relative reactivity toward S N 2 substitution (R LiI in acetone, 25 C) C 3 very slow 1 1, ,000 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 8.2, 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 approach of the nucleophile and causes ethyl bromide to be less reactive than methyl bromide. Replacing all three hydrogens by methyl

9 314 Chapter 8 Nucleophilic Substitution Figure 8.2 Ball-and-spoke (top) and space-filling (bottom) 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. Least crowded most reactive Most crowded least reactive C 3 C 3 C 2 (C 3 ) 2 C (C 3 ) 3 C groups almost completely blocks approach to the tertiary carbon of (C 3 ) 3 C and shuts down bimolecular nucleophilic substitution. In general, S N 2 reactions of alkyl halides show the following dependence of rate on structure: C 3 X > primary > secondary > tertiary. Problem 8.7 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-omopentane or 3-bromopentane (c) 2-Chloropentane or 2-fluoropentane (d) 2-omo-2-methylhexane or 2-bromo-5-methylhexane (e) 2-omopropane 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 S N 2 mechanism. 1-Chlorohexane is more reactive. 1-Chlorohexane (primary, more reactive) Cyclohexyl chloride (secondary, less reactive) Alkyl groups at the carbon atom adjacent to the point of nucleophilic attack also decrease the rate of the S N 2 reaction. 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. When C-2 is completely substituted by methyl groups, as it is in neopentyl bromide [(C 3 ) 3 CC 2 ], we see the unusual case of a primary alkyl halide that is practically inert to substitution by the S N 2 mechanism because of steric hindrance. Neopentyl bromide (1-omo-2,2-dimethylpropane)

10 8.5 Nucleophiles and Nucleophilicity 315 Increasing relative reactivity toward S N 2 substitution (R LiI in acetone, 25 C) Problem The reaction shown, when carried out with 1,4-dibromopentane, is the first step in the synthesis of the antimalarial drug primaquine. It proceeds by an S N 2 mechanism and gives a compound having the molecular formula C N 2. What is this compound? NK R NR K 8.5 Nucleophiles and Nucleophilicity The Lewis base that acts as the nucleophile often is, but need not always be, an anion. Neutral Lewis bases such as amines (R 3 N:), phosphines (R 3 P:), and sulfides (R 2 S :) can also serve as nucleophiles. 3 C S 3 C Dimethyl sulfide C 3 I Methyl iodide 3 C S C I 3 3 C Trimethylsulfonium iodide ther common examples of substitutions involving neutral nucleophiles include solvolysis reactions substitutions where the nucleophile is the solvent in which the reaction is carried out. Solvolysis in water (hydrolysis) converts an alkyl halide to an alcohol. RX Alkyl halide 2 2 Water R Alcohol 3 ydronium ion X alide ion The reaction occurs in two steps. The first yields an alkyloxonium ion by nucleophilic substitution and is rate-determining. The second gives the alcohol by proton transfer a rapid ønsted acid base reaction. slow 2 R X X R fast Water Alkyl halide alide ion Alkoxonium ion Alcohol R 3 ydronium ion Analogous reactions take place in other solvents that, like water, contain an group. Solvolysis in methanol (methanolysis) gives a methyl ether. 3 C Methanol R X slow C 3 X R fast 3 C 3 C Alkyl halide alide ion Alkylmethyloxonium ion Alkyl methyl ether R C3 2 Methyloxonium ion

11 316 Chapter 8 Nucleophilic Substitution TABLE 8.2 Nucleophilicity of Some Common Nucleophiles Reactivity class Nucleophile Relative reactivity* Very good nucleophiles l, S, RS >10 5 Good nucleophiles,, R, CN, N Fair nucleophiles N 3,, F, RC Weak nucleophiles 2, R 1 Very weak nucleophiles RC * Relative reactivity is k(nucleophile)/k(methanol) for typical S N 2 reactions and is approximate. Data pertain to methanol as the solvent. Because attack by the nucleophile is the rate-determining step of the S N 2 mechanism, the rate of substitution varies from nucleophile to nucleophile. Nucleophilic strength, or nucleophilicity, is a measure of how fast a Lewis base displaces a leaving group from a suitable substrate. Table 8.2 compares the rate at which various Lewis bases react with methyl iodide in methanol, relative to methanol as the standard nucleophile. As long as the nucleophilic atom is the same, the more basic the nucleophile, the more reactive it is. An alkoxide ion (R ) is more basic and more nucleophilic than a carboxylate ion (RC 2 ). R± Stronger base Conjugate acid is R: pk a 16 is more nucleophilic than X RC± Weaker base Conjugate acid is RC 2 : pk a 5 The connection between basicity and nucleophilicity holds when comparing atoms in the same row of the periodic table. Thus, is more basic and more nucleophilic than F, and 3 N is more basic and more nucleophilic than 2. 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 ion dipole forces of the type illustrated in Figure 8.3. 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, ion dipole forces are strongest for F and weakest for I. Thus, the nucleophilicity of F is suppressed more than that of, more than, and more than I. Similarly, is smaller, more solvated, and less nucleophilic than S. The importance of solvation in reducing the nucleophilicity of small anions more than larger ones can be seen in the fact that, when measured in the gas phase where solvation forces don t exist, the order of halide nucleophilicity reverses and tracks basicity: F > > > I. When comparing species that have the same nucleophilic atom, a negatively charged nucleophile is more reactive than a neutral one. R± is more nucleophilic than R±± Alkoxide ion Alcohol Figure 8.3 X RC± is more nucleophilic than X R±C±± Solvation of a chloride ion by water. Carboxylate ion Carboxylic acid

12 8.6 The S N 1 Mechanism 8.5 Nucleophiles of Nucleophilic and Nucleophilicity Substitution 317 Enzyme-Catalyzed Nucleophilic Substitutions of Alkyl alides 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 the dehalogenase shown in Figure dehalogenase This haloalkane dehalogenase is believed to act by covalent catalysis using one of its side-chain carboxylates to displace chloride by an S N 2 mechanism. Enzyme Enzyme S N The product of nucleophilic substitution then reacts with water, restoring the enzyme to its original state and giving the observed products of the reaction. 2 (S)-2-Chloropropanoic acid dehalogenase Racemic 2-chloropropanoic acid (S)-Lactic acid In this enzymatic resolution, the dehalogenase enzyme catalyzes the hydrolysis of the R-enantiomer of 2-chloropropanoic acid to (S)-lactic acid. The desired (S)-2-chloropropanoic acid is unaffected and recovered in a nearly enantiomerically pure state. Some of the most common biological S N 2 reactions involve attack at methyl groups, especially the methyl group of S-adenosylmethionine. Examples of these will be given in Chapter 16. Enzyme 2 several steps Enzyme Both stages of the mechanism are faster than the hydrolysis of 1,2-dichloroethane in the absence of the enzyme. Enzyme-catalyzed hydrolysis of racemic 2-chloropropanoic acid is a key step in the large-scale preparation (2000 tons per year!) of (S)-2-chloropropanoic acid used in the production of agricultural chemicals. Figure 8.4 A ribbon diagram of the dehalogenase enzyme that catalyzes the hydrolysis of 1,2-dichloroethane. The progression of amino acids along the chain is indicated by a color change. The nucleophilic carboxylate group is near the center of the diagram. 8.6 The S N 1 Mechanism of Nucleophilic Substitution aving seen that tertiary alkyl halides are practically inert to substitution by the S N 2 mechanism because of steric hindrance, we might wonder whether they undergo nucleophilic substitution at all. They do, but by a different mechanism. In their studies of reaction kinetics, ughes and Ingold observed that the hydrolysis of tert-butyl bromide follows a first-order rate law: (C 3 ) 2 C tert-butyl bromide 2 2 (C 3 ) 2 C 3 Water tert-butyl alcohol ydronium ion Rate k[(c 3 ) 3 ] omide ion

13 318 Chapter 8 Nucleophilic Substitution The reaction rate depends only on the concentration of tert-butyl bromide. Just as ughes and Ingold interpreted a second-order rate law in terms of a bimolecular rate-determining step, they saw first-order kinetics as evidence for a unimolecular rate-determining step one that involves only the alkyl halide and is independent of both the concentration and identity of the nucleophile. Like the mechanism for the reaction of alcohols with hydrogen halides (Section 4.8), this pathway is classified as S N 1 (substitution-nucleophilic- unimolecular) and is characterized by the formation of a carbocation in the rate-determining step. The S N 1 mechanism for the hydrolysis of tert-butyl bromide is presented as a series of elementary steps in Mechanism 8.2, as a potential energy diagram in Figure 8.5, and in abbreviated form as: slow (C 3 ) 3 C (C 3 ) 3 C 2 2 (C 3 fast 3 ) 3 C (C 3 ) 3 C fast tert-butyl bromide omide ion tert-butyl cation tert-butyloxonium ion tert-butyl alcohol ydronium ion The key step is the first: a rate-determining unimolecular ionization of the alkyl halide to give a carbocation and a halide ion. Following this, capture of the carbocation by a water molecule acting as a nucleophile gives an alkyloxonium ion, which is then deprotonated by a second water molecule acting as a ønsted base to complete the process. Mechanism 8.2 The S N 1 Mechanism of Nucleophilic Substitution TE VERALL REACTIN: tert-butyl bromide Water tert-butyl alcohol ydronium ion omide ion TE MECANISM: Step 1: The alkyl halide dissociates to a carbocation and a halide ion. slow tert-butyl bromide tert-butyl cation omide ion Step 2: The carbocation formed in step 1 reacts rapidly with water, which acts as a nucleophile. This step completes the nucleophilic substitution stage of the mechanism and yields an alkyloxonium ion. tert-butyl cation Water tert-butyloxonium ion Step 3: This step is a fast acid base reaction that follows the nucleophilic substitution. Water acts as a base to remove a proton from the alkyloxonium ion to give the observed product of the reaction, tert-butyl alcohol. tert-butyloxonium ion Water tert-butyl alcohol ydronium ion

14 8.6 The S N 1 Mechanism 8.5 Nucleophiles of Nucleophilic and Nucleophilicity Substitution 319 δ 2 2 δ 2 δ δ Figure 8.5 Energy diagram illustrating the S N 1 mechanism for hydrolysis of tert-butyl bromide. E a Potential energy 2 2 δ δ Reaction coordinate In order to compare S N 1 rates in a range of alkyl halides, experimental conditions of low nucleophilicity such as solvolysis are chosen so as to suppress competition from S N 2. Under these conditions, the structure/reactivity trend among alkyl halides is exactly opposite to the S N 2 profile. Increasing relative reactivity toward solvolysis (aqueous formic acid) C ~100,000,000 S N 1 reactivity: methyl < primary < secondary < tertiary We have seen a similar trend in the reaction of alcohols with hydrogen halides (Section 4.10), in the acid-catalyzed dehydration of alcohols (Section 5.12), and in the conversion of alkyl halides to alkenes by the E1 mechanism (Section 5.18). As in these other reactions, the more stable the carbocation, the faster it is formed, and the faster the reaction rate. Methyl and primary carbocations are so high in energy that they are unlikely intermediates in nucleophilic substitutions. Although methyl and ethyl bromide undergo hydrolysis under the conditions just described, substitution probably takes place by an S N 2 process in which water is the nucleophile. In general, methyl and primary alkyl halides never react by the S N 1 mechanism; tertiary alkyl halides never react by S N 2. Secondary alkyl halides occupy a borderline region in which the nature of the nucleophile is the main determining factor in respect to the mechanism. Secondary alkyl halides usually react with good nucleophiles by the S N 2 mechanism, and with weak nucleophiles by S N 1. Problem 8.9 Identify the compound in each of the following pairs that reacts at the faster rate in an S N 1 reaction: (a) Isopropyl bromide or isobutyl bromide (b) Cyclopentyl iodide or 1-methylcyclopentyl iodide (c) Cyclopentyl bromide or 1-bromo-2,2-dimethylpropane (d) tert-butyl chloride or tert-butyl iodide Continued

15 320 Chapter 8 Nucleophilic Substitution Sample Solution (a) Isopropyl bromide, (C 3 ) 2 C, is a secondary alkyl halide, whereas isobutyl bromide, (C 3 ) 2 CC 2, is primary. Because the rate-determining step in an S N 1 reaction is carbocation formation and secondary carbocations are more stable than primary ones, isopropyl bromide is more reactive than isobutyl bromide in nucleophilic substitution by the S N 1 mechanism. Problem 8.10 Numerous studies of their solvolysis reactions (S N 1) have established the approximate rates of nucleophilic substitution in bicyclic compounds A and B relative to their tert-butyl counterpart, where X is a halide or sulfonate leaving group. X X X tert-butyl: 1 A: 10 6 B: Suggest a reasonable explanation for the very large spread in reaction rates. 8.7 Stereochemistry of S N 1 Reactions Although S N 2 reactions are stereospecific and proceed with inversion of configuration at carbon, the situation is not as clear-cut for S N 1. When the leaving group departs from a chirality center of an optically active halide, the positively charged carbon that results is sp 2 -hybridized and cannot be a chirality center. The three bonds to that carbon define a plane of symmetry. : Alkyl halide is chiral Carbocation is achiral If a nucleophile can approach each face of the carbocation equally well, substitution by the S N 1 mechanism should give a 1:1 mixture of enantiomers irrespective of whether the starting alkyl halide is R, S, or racemic. S N 1 reactions should give racemic products from optically active starting materials. But they rarely do. Methanolysis of the tertiary alkyl halide (R)-3-chloro-3,7- dimethyloctane, which almost certainly proceeds by an S N 1 mechanism, takes place with a high degree of inversion of configuration. C 3 C 3 C 3 (R)-3-Chloro-3,7- dimethyloctane (S)-3,7-Dimethyl-3- methoxyoctane (89%) (R)-3,7-Dimethyl-3- methoxyoctane (11%) Similarly, hydrolysis of (R)-2-bromooctane follows a first-order rate law and yields 2- octanol with 66% net inversion of configuration. Partial but not complete loss of optical activity in S N 1 reactions is explained as shown in Figure 8.6. The key feature of this mechanism is that when the carbocation is formed, it is not completely free of the leaving group. Although ionization is complete, the leaving group has not yet diffused very far away from the carbon to which it was attached and partially blocks approach of the nucleophile from that direction. Nucleophilic attack on this species, called an ion pair, occurs faster from the side opposite the leaving group. nce the leaving group has diffused away, however, both faces of the carbocation are equally accessible to nucleophiles and equal quantities of enantiomeric products result.

16 8.8 Carbocation 8.7 Stereochemistry Rearrangements of in SN1 S N 1 Reactions 321 Ionization Carbocation/Leaving group ion pair : Leaving group shields front side of carbocation; nucleophile attacks faster from back. More inversion of configuration than retention. : : Separation of carbocation and anion of leaving group Carbocation : : Carbocation free of leaving group; nucleophile attacks either side of carbocation at same rate. Product is racemic. : Figure 8.6 S N 1 stereochemistry. The carbocation formed by ionization of an alkyl halide is shielded on its front side by the leaving group. The nucleophile attacks this carbocation-halide ion pair faster from the less shielded back side and the product is formed with net inversion of configuration. In a process that competes with nucleophilic attack on the ion pair, the leaving group diffuses away from the carbocation. The nucleophile attacks the carbocation at the same rate from either side to give equal amounts of enantiomers. More than 50% Less than 50% 50% 50% The stereochemistry of S N 1 substitution depends on the relative rates of competing processes attack by the nucleophile on the ion pair versus separation of the ions. Consequently, the observed stereochemistry varies considerably according to the alkyl halide, nucleophile, and experimental conditions. Some give predominant, but incomplete, inversion of configuration. thers give products that are almost entirely racemic. Problem 8.11 What two stereoisomeric substitution products would you expect to isolate from the hydrolysis of cis-1,4-dimethylcyclohexyl bromide? From hydrolysis of trans-1,4-dimethylcyclohexyl bromide? 8.8 Carbocation Rearrangements in S N 1 Reactions Additional evidence for carbocation intermediates in certain nucleophilic substitutions comes from observing rearrangements of the kind normally associated with such species. For example, hydrolysis of the secondary alkyl bromide 2-bromo-3-methylbutane yields the rearranged tertiary alcohol 2-methyl-2-butanol as the only substitution product. 2 2-omo-3-methylbutane 2-Methyl-2-butanol (93%) Mechanism 8.3 for this reaction assumes rate-determining ionization of the alkyl halide (step 1), followed by a hydride shift that converts a secondary carbocation to a more stable tertiary one (step 2). The tertiary carbocation then reacts with water to yield the observed product (steps 3 and 4). Problem 8.12 Why does the carbocation intermediate in the hydrolysis of 2-bromo-3-methylbutane rearrange by way of a hydride shift rather than a methyl shift? Rearrangements, when they do occur, are taken as evidence for carbocation intermediates and point to the S N 1 mechanism as the reaction pathway. Rearrangements are never observed in S N 2 reactions of alkyl halides.

17 322 Chapter 8 Nucleophilic Substitution Mechanism 8.3 Carbocation Rearrangement in the S N 1 ydrolysis of 2-omo-3-methylbutane TE VERALL REACTIN: omo-3-methylbutane Water 2-Methyl-2-butanol ydronium ion omide ion TE MECANISM: Step 1: The alkyl halide ionizes to give a carbocation and bromide ion. This is the rate-determining step. slow 2-omo-3-methylbutane 1,2-Dimethylpropyl cation omide ion Step 2: The carbocation formed in step 1 is secondary; it rearranges by a hydride shift to form a more stable tertiary carbocation. 1,2-Dimethylpropyl cation fast 1,1-Dimethylpropyl cation Step 3: The tertiary carbocation is attacked by water acting as a nucleophile. fast 1,1-Dimethylpropyl cation Water 1,1-Dimethylpropyloxonium ion Step 4: Proton transfer from the alkyloxonium ion to water completes the process. fast 1,1-Dimethylpropyloxonium ion Water 2-Methyl-2-butanol ydronium ion 8.9 Effect of Solvent on the Rate of Nucleophilic Substitution The major effect of the solvent is on the rate of nucleophilic substitution, not on what the products are. Thus we need to consider two related questions: 1. What properties of the solvent influence the rate most? 2. ow does the rate-determining step of the mechanism respond to the properties of the solvent?

18 8.9 Effect of Solvent on the Rate of Nucleophilic Substitution 323 TABLE 8.3 Properties of Some Solvents Used in Nucleophilic Substitution Solvent Structural formula Protic or Aprotic Dielectric constant ε* Polarity Water 2 Protic 78 Most polar Formic acid B C Protic 58 Dimethyl sulfoxide (C 3 ) 2 S ± Aprotic 49 Acetonitrile C 3 CPN Aprotic 37 N,N-Dimethylformamide B (C 3 ) 2 NC Aprotic 37 Methanol C 3 Protic 33 Acetic acid B C 3 C Protic 6 Least polar * Dielectric constants are approximate and temperature-dependent. We begin by looking at the solvents commonly employed in nucleophilic substitutions, then proceed to examine how these properties affect the S N 1 and S N 2 mechanisms. Because these mechanisms are so different from each other, we discuss each one separately. asses of Solvents. Table 8.3 lists a number of solvents in which nucleophilic substitutions are carried out and classifies them according to two criteria: whether they are protic or aprotic, and polar or nonpolar. Protic solvents are those that are capable of hydrogen-bonding interactions. Most have groups, as do the examples in Table 8.3 (water, formic acid, methanol, and acetic acid). The aprotic solvents in the table (dimethyl sulfoxide, N,N-dimethylformamide, and acetonitrile) lack groups. The polarity of a solvent is related to its dielectric constant (ε), which is a mea sure of the ability of a material to moderate the force of attraction between oppositely charged particles. The standard dielectric is a vacuum, assigned a value ε of exactly 1, to which the polarities of other materials are then compared. The higher the dielectric constant ε, the better the medium is able to support separated positively and negatively charged species. Solvents with high dielectric constants are classified as polar solvents; those with low dielectric constants are nonpolar. Unlike protic and aprotic, which constitute an either-or pair, polar and nonpolar belong to a continuous gradation with no sharply defined boundary separating them. Problem 8.13 Diethyl ether (C 3 C 2 C 2 C 3 ) has a dielectric constant of 4. What best describes its solvent properties: polar protic, nonpolar protic, polar aprotic, or nonpolar aprotic? Solvent Effects on the Rate of Substitution by the S N 2 Mechanism. Polar solvents are required in typical bimolecular substitutions because ionic substances, such as the sodium and potassium salts cited earlier in Table 8.1, are not sufficiently soluble in nonpolar solvents to give a high enough concentration of the nucleophile to allow the reaction to occur at a rapid rate. ther than the requirement that the solvent be polar enough to dissolve ionic compounds, however, the effect of solvent polarity on the rate of S N 2 reactions is small. What is more important is whether the polar solvent is protic or aprotic. Protic

19 324 Chapter 8 Nucleophilic Substitution solvents such as water, formic acid, methanol, and acetic acid all have groups that allow them to form hydrogen bonds to anionic nucleophiles. R± Solvent Y Nucleophile R±,Y ydrogen-bonded complex This clustering of protic solvent molecules (solvation) around an anion supresses its nucleophilicity and retards the rate of bimolecular substitution. Aprotic solvents, on the other hand, lack groups and do not solvate anions very strongly, leaving the anions much more able to express their nucleophilic character. Table 8.4 compares the second-order rate constants k for S N 2 substitution of 1-bromobutane by azide ion (a good nucleophile) in several polar aprotic solvents with the corresponding k s for the much slower reactions in polar protic solvents. N N 3 3 Butyl bromide Azide ion Butyl azide omide ion Problem 8.14 Unlike protic solvents, which solvate anions, polar aprotic solvents form complexes with cations better than with anions. Use a dashed line to show the interaction between dimethyl sulfoxide [(C 3 ) 2 S ± ] with a cation, using sodium azide (NaN 3 ) as the source of the cation. The large rate enhancements observed for bimolecular nucleophilic substitutions in polar aprotic solvents offer advantages in synthesis. ne example is the preparation of alkyl cyanides (nitriles) by the reaction of sodium cyanide with alkyl halides: exyl halide X NaCN CN NaX Sodium cyanide exyl cyanide Sodium halide When the reaction was carried out in aqueous methanol as the solvent, hexyl bromide was converted to hexyl cyanide in 71% yield. Although this is perfectly acceptable for a synthetic reaction, it required heating for a period of over 20 hours. Changing the solvent to dimethyl sulfoxide increased the reaction rate to the extent that the less reactive (and less expensive) hexyl chloride could be used and the reaction was complete (91% yield) in only 20 minutes! TABLE 8.4 Relative Rate of S N 2 Displacement of 1-omobutane by Azide in Various Solvents* Solvent Structural formula Dielectric constant ε Type of solvent Relative rate Methanol C 3 33 Polar protic 1 Water 2 78 Polar protic 7 Dimethyl sulfoxide (C 3 ) 2 S ± 49 Polar aprotic 1300 N,N-Dimethylformamide B (C 3 ) 2 NC 37 Polar aprotic 2800 Acetonitrile C 3 CPN 37 Polar aprotic 5000 * Ratio of second-order rate constant for substitution in indicated solvent to that for substitution in methanol at 25 C.

20 8.9 Effect of Solvent on the Rate of Nucleophilic Substitution 325 The rate at which reactions occur can be important in the laboratory, and understanding how solvents affect rate is of practical value. As we proceed through the text, however, and see how nucleophilic substitution is applied to a variety of functional group transformations, be aware that the nature of both the substrate and the nucleophile, more than anything else, determines what product is formed. Solvent Effects on the Rate of Substitution by the S N 1 Mechanism. Table 8.5 gives the relative rate of solvolysis of tert-butyl chloride in several protic solvents listed in order of increasing dielectric constant. As the table illustrates, the rate of solvolysis of tert-butyl chloride (which is equal to its rate of ionization) increases dramatically as the solvent becomes more polar. According to the S N 1 mechanism, a molecule of an alkyl halide ionizes to a positively charged carbocation and a negatively charged halide ion in the rate-determining step. As the alkyl halide approaches the transition state for this step, positive charge develops on the carbon and negative charge on the halogen. The effects of a nonpolar and a polar solvent on the energy of the transition state are contrasted in Figure 8.7. Polar and nonpolar solvents are similar in their interaction with the starting alkyl halide, but differ markedly in how they stabilize the transition state. A solvent with a low dielectric constant has little effect on the energy of TABLE 8.5 Relative Rate of S N 1 Solvolysis of tert-butyl Chloride as a Function of Solvent Polarity* Solvent Dielectric constant ε Relative rate Acetic acid 6 1 Methanol 33 4 Formic acid 58 5,000 Water ,000 *Ratio of first-order rate constant for solvolysis in indicated solvent to that for solvolysis in acetic acid at 25 C. ± ± ± δ R δ X ± ± ± Transition state is more polar than starting state; polar solvent can cluster about transition state so as to reduce electrostatic energy associated with separation of opposite charges. δ δ R X Figure 8.7 A polar solvent stabilizes the transition state of an S N 1 reaction and increases its rate. E act E act ± ± ± R X ± Energy of alkyl halide is approximately the same in either a nonpolar or a polar solvent. R X ± ± Nonpolar solvent Polar solvent

21 326 Chapter 8 Nucleophilic Substitution the transition state, whereas one with a high dielectric constant stabilizes the charge-separated transition state, lowers the activation energy, and increases the rate of the reaction. If the solvent, like those listed in Table 8.4, is protic, stabilization of the transition state is even more pronounced because of the hydrogen bonding that develops as the leaving group becomes negatively charged Substitution and Elimination as Competing Reactions We have seen that a Lewis base can react with an alkyl halide by either substitution or elimination. C C X Y elimination nucleophilic substitution C C Y X C C X Y Substitution can take place by the S N 1 or the S N 2 mechanism, elimination by E1 or E2. ow can we predict whether substitution or elimination will predominate? The two most important factors are the structure of the alkyl halide and the basicity of the anion. It is useful to approach the question from the premise that the characteristic reaction of alkyl halides with Lewis bases is elimination, and that substitution predominates only under certain special circumstances. In a typical reaction, a secondary alkyl halide such as isopropyl bromide reacts with a Lewis base such as sodium ethoxide mainly by elimination: NaC 2 C 3 C 3 C 2, 55 C Isopropyl bromide Propene (87%) Ethyl isopropyl ether (13%) Figure 8.8 illustrates the close relationship between the E2 and S N 2 pathways for this case, and the results cited in the preceding equation clearly show that E2 is faster than S N 2 when a secondary alkyl halide reacts with a strong base. As crowding at the carbon that bears the leaving group decreases, the rate of nucleophilic substitution becomes faster than the rate of elimination. A low level of steric hindrance to approach of the nucleophile is one of the special circumstances that permit substitution to predominate, and primary alkyl halides react with alkoxide bases by an S N 2 mechanism in preference to E2: NaC 2 C 3 C 3 C 2, 55 C Propyl bromide Propene (9%) Ethyl propyl ether (91%) Figure 8.8 When a Lewis base reacts with an alkyl halide, either substitution or elimination can occur. Substitution (S N 2) occurs when the Lewis base acts as a nucleophile and attacks carbon to displace bromide. Elimination (E2) occurs when the Lewis base abstracts a proton from the β carbon. The alkyl halide shown is isopropyl bromide, and elimination (E2) predominates over substitution with alkoxide bases. C 3 C 2 E2 S N 2 C

22 8.10 Substitution and Elimination as Competing Reactions 327 If, however, the base itself is crowded, such as potassium tert-butoxide, even primary alkyl halides undergo elimination rather than substitution: C 3 (C 2 ) 15 C 2 C 2 1-omooctadecane KC(C 3 ) 3 (C 3 ) 3 C, 40 C C 3(C 2 ) 15 C C 2 1-ctadecene (87%) C 3 (C 2 ) 15 C 2 C 2 C(C 3 ) 3 tert-butyl octadecyl ether (13%) A second factor that can tip the balance in favor of substitution is weak basicity of the nucleophile. Nucleophiles that are less basic than hydroxide react with both primary and secondary alkyl halides to give the product of nucleophilic substitution in high yield. To illustrate, cyanide ion is much less basic than hydroxide and reacts with 2-chlorooctane to give the corresponding alkyl cyanide as the major product. Cyanide is a weaker base than hydroxide because its conjugate acid CN (pk a 9.1) is a stronger acid than water (pk a 15.7). KCN DMS CN 2-Chlorooctane 2-Cyanooctane (70%) Azide ion NœNœN is an even weaker base than cyanide. It is a good nucleophile and reacts with secondary alkyl halides mainly by substitution: The conjugate acid of azide ion is called hydrazoic acid (N 3 ). It has a pk a of 4.6, and so is similar to acetic acid in its acidity. I NaN 3 N N N Cyclohexyl iodide Cyclohexyl azide (75%) ydrogen sulfide ion S, and anions of the type RS, are substantially less basic than hydroxide ion and react with both primary and secondary alkyl halides to give mainly substitution products. Tertiary alkyl halides are so sterically hindered to nucleophilic attack that the presence of any anionic Lewis base favors elimination. Usually substitution predominates over elimination in tertiary alkyl halides only when anionic Lewis bases are absent. In the solvolysis of the tertiary bromide 2-bromo-2-methylbutane, for example, the ratio of substitution to elimination is 64:36 in pure ethanol but falls to 1:99 in the presence of 2 M sodium ethoxide. ydrogen sulfide (pk a 7.0) is a stronger acid than water (pk a 15.7). Therefore S is a much weaker base than. C 2 C 3 ethanol 25 C 2-omo-2- methylbutane 2-Ethoxy-2- methylbutane (Major product in absence of sodium ethoxide) 2-Methyl-2-butene 2-Methyl-1-butene (Alkene mixture is major product in presence of sodium ethoxide) The substitution product in this case is formed by an S N 1 mechanism both in the presence and absence of sodium ethoxide. The alkenes are formed by an E1 mechanism in the absence of sodium ethoxide and by a combination of E2 (major) and E1 (minor) in its presence. Problem 8.15 Predict the major organic product of each of the following reactions: (a) Cyclohexyl bromide and potassium ethoxide (b) Ethyl bromide and potassium cyclohexanolate (c) sec-butyl bromide solvolysis in methanol (d) sec-butyl bromide solvolysis in methanol containing 2 M sodium methoxide Continued