Baixe Carey - Organic Chemistry - chapt08 e outras Manuais, Projetos, Pesquisas em PDF para Química, somente na Docsity! CHAPTER 8 NUCLEOPHILIC SUBSTITUTION 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. Wy's we discussed elimination reactions in Chapter 5, we learned that a Lewis RXE+ O YD o —>S> R>Y + Alkyl Lewis base Product of Halide halide 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'1l 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 in 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 302 that bond are lost with the leaving group. Back| 8.1 Functional Group Transformation by Nucleophilic Substitution — i a+ 8 The carbon - halogen bond in RX X=L Br. CLF 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 vo ROK: Ss R>Y +:X7 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 MOR (a metal alkoxide, a source of the nucleophilic anion RÔ o o :0: | MOCR (a metal carboxylate, a source of the nucleophilic anion RC—C MSH (a metal hydrogen sulfide, a source of the nucleophilic anion Há MCN (a metal cyanide, a source of the nucleophilic anion :C=N3 - + À MN: (a metal azide, a source of the nucleophilic anion : N =N=N3) Table 8.1 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 metal cation portion becomes a lithium, sodium, or potassium halide. A micy+RÉkES Roy + Mt Nucleophilic Alkyl Product of Metal halide reagent 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 halides, compounds in which the halogen is attached to sp?-hybridized carbons, are 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 c — as Y >x / DS: Alkyl halide Alkenyl halide Aryl 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- quently 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 nucle- ophilic substitution reactions. 303 Alkenyl halides are also re- ferred to as vinylic halides. The use of DMSO as a sol- vent in dehydrohalogenation reactions was mentioned earlier, in Section 5.14. Forward Main Menul Toe] Study Guide TOC Student OLC MHHE Website 306 CHAPTER EIGHT | Nucleophilic Substitution Increasing rate of substitution by nucleophiles RF < RC < RBr < RI Least reactive Most reactive 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 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 than alkyl chlorides. PROBLEM 8.2 A single organic product was obtained when 1-bromo-3-chloro- propane was allowed to react with one molar equivalent of sodium cyanide in aqueous ethanol. What was this product? Rapel tonsp Denusen Leaving-group ability is also related to basicity. A strongly basic anion is usually leaving group ability and ba- a poorer leaving group than a weakly basic one. Fluoride is the most basic and the poor- slcity is explored in more de, est leaving group among the halide anions, iodide the least basic and the best leaving tail in Section 8.14. group 8.3 THE Sy2 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 hydrox- ide reacts with methyl bromide to form methyl alcohol and sodium bromide: CHsBr + HO” —>.. CH;)0H + 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- order overall. Rate = KCH;Brl[HO”] 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 are involved at the transition state. The symbol given to the detailed description of the mech- RSS 2 mechanism as anism that they developed is Sx2, standing for substitution nucleophilic bimolecular. troduced earlier in Section The Hughes and Ingold Sx2 mechanism is a single-step process in which both the 413. 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 E Forward Main Menul Toe] Study Guide TOC) Student OLC| MHHE Website Back| 84 — Stereochemistry of Sy2 Reactions its point of attachment to carbon. For this reason, the Sx2 mechanism is sometimes referred to as a direct displacement process. The Sx2 mechanism for the hydrolysis of methyl bromide may be represented by a single elementary step: 8- 8— HO + CH;Br: — HO-CH;--Br: — HÓCH; + Hydroxide Methyl Transition Methyl — Bromide ion bromide state alcohol ion 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? Il cHBr DD cH;* + Br fi cHs* + HO LÊ» cH;OH The Sx2 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 Sx2 mechanism (or a mechanism very much like Sy2-— remember, mechanisms can never be established with certainty but represent only our best present explanations of experimental observations). We"ll examine the Sy2 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 Sy2 REACTIONS What is the structure of the transition state in an Sy2 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 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. mM 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 halide. CHACHos dE em E (CHo)sCH, C—Br “ahanolwarer” HO-—C HC CH; (S)h(+)2-Bromooctane (R)(—)-2-Octanol 307 Although the alkyl halide and alcohol given in this ex- ample have opposite config- urations when they have opposite signs of rotation, it cannot be assumed that this will be true for all alkyl halide/alcohol pairs. (See Sec- tion 7.5) Forward Main Menul Toe] Study Guide TOC Student OLC MHHE Website 308 FIGURE 8.1 Two contrasting stereochemical pathways for substitution of a leaving group (red) by a nucleophile (blue). In (a) the nudeophile attacks carbon at the same side from which the leaving group departs. In (b) nucle- ophilic attack occurs at the side opposite the bond to the leaving group. For a change of pace, try ê doing Problem 8.4 with molecu- lar models instead of making structural drawings. The first example of a stereo- electronic effectiin this text concerned anti elimination in E2 reactions of alkyl halides (Section 5.16). E Forward Main Menul CHAPTER EIGHT | Nucleophilic Substitution peepa pe (a) Nucleophilic substitution with retention of configuration º Nucleophilic substitution had occurred with inversion of configuration, consistent with the following transition state: e po-é 3 é-o (b) Nucleophilic substitution with inversion of configuration CHs(CHo)s 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. CHs Br CHa(CHoJaCHa PROBLEM 8.5 Would you expect the 2-octanol formed by Sy2 hydrolysis of (—)- 2-bromooctane to be optically active? If so, what will be its absolute configura- tion 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 Sx2 mechanism is stereospecific and proceeds with inversion of con- figuration at the carbon that bears the leaving group. There is a stereoelectronic require- ment for the nucleophile to approach carbon from the side opposite the bond to the leav- ing 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 Sy2 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 Sx2 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. TOC| Study Guide TOC] — Student OLC MHHE Website Back| 86 — Steric Effects in Sy2 Reactions Least crowded-— Most crowded- most reactive least reactive 9 q co P S a s “ee c CH;Br CH;CH;Br (CH;)CHBr nte (CHa)sCBr 288 & O 8.3 Ball-and-spoke and space-filling models of alkyl bromides, showing how sub- stituents 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. 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-Chloro- hexane 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 Sy2 mechanism. 1-Chlorohexane is more reactive. H CHCH>CH>CH>CH>CH>CI (a 1-Chlorohexane Cyclohexyl chloride (primary, more reactive) (secondary, less reactive) Alkyl groups at the carbon atom adjacent to the point of nucleophilic attack also decrease the rate of the Sx2 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 car- bon that bears the leaving group, but it is still substantial. When C-2 is completely sub- stituted by methyl groups, as it is in neopentyl bromide [(CH;)3CCH>Br], we see the unusual case of a primary alkyl halide that is practically inert to substitution by the Sx2 mechanism because of steric hindrance. Forward Main Menul Toe] Study Guide TOC Student OLC 31 MHHE Website 312 CHAPTER EIGHT | Nucleophilic Substitution TABLE Effect of Chain Branching on Reactivity of Primary Alkyl Bromides Toward Substitution Under Sy2 Conditions* Alkyl bromide Structure Relative rate! Ethyl bromide CHsCH,Br 1.0 Propyl bromide CHsCH>CH,Br 0.8 Isobutyl bromide (CH3)>CHCH,Br 0.036 Neopentyl bromide (CH3)3CCH>Br 0.00002 *Substitution of bromide by lithium iodide in acetone. *Ratio of second-order rate constant k for indicated alkyl bromide to k for ethyl bromide at 25ºC. 8.7 | NUCLEOPHILES AND NUCLEOPHILICITY The Lewis base that acts as the nucleophile often is, but need not always be, an anion. Neutral Lewis bases can also serve as nucleophiles. Common examples of substitutions involving neutral nucleophiles include solvolysis reactions. Solvolysis reactions are sub- stitutions in which the nucleophile is the solvent in which the reaction is carried out. Solvolysis in water converts an alkyl halide to an alcohol. H H No N& = jo/+ rx LL Cor + x > RÔH + HX La “ H H Water Alkyl Alkyloxonium Alcohol — Hydrogen halide halide halide Solvolysis in methyl alcohol converts an alkyl halide to an alkyl methyl ether. EC ss HC, jo + ROX LD JOR + X- > RÓCH, + HX B so O H H Methyl alcohol Alkyl Dialkyloxonium Alkyl Hydtogen halide halide methyl ether halide Im these and related solvolyses, the first stage is the one in which nucleophilic substitution takes place and is rate-determining. The proton-transfer step that follows it is much faster. Since, as we have seen, the nucleophile attacks the substrate in the rate- determining step of the Sy2 mechanism, it follows that the rate at which substitution occurs may vary from nucleophile to nucleophile. Just as some alkyl halides are more reactive than others, some nucleophiles are more reactive than others. Nucleophilic strength, or nucleophilicity, is a measure of how fast a Lewis base displaces a leaving group from a suitable substrate. By measuring the rate at which various Lewis bases react with methyl iodide in methanol, a list of their nucleophilicities relative to methanol as the standard nucleophile has been compiled. It is presented in Table 8.4. Neutral Lewis bases such as water, alcohols, and carboxylic acids are much weaker nucleophiles than their conjugate bases. When comparing species that have the same nucleophilic atom, a negatively charged nucleophile is more reactive than a neutral one. Back| Forward Main Menul Toe] Study Guide TOC Student OLC MHHE Website Back| 87 Nucleophiles and Nucleophilicity 313 END Nucleophilicity of Some Common Nucleophiles Reactivity class Nucleophile Relative reactivity* Very good nucleophiles 1, HST, RS >10º Good nucleophiles Br,HO,RO, CN, Ns 104 Fair nucleophiles NHa, CI”, F, RCO> 102 Weak nucleophiles H,0, ROH 1 Very weak nucleophiles RCO,H 102 *Relative reactivity is k(nucleophile)/k(methano!) for typical Sw2 reactions and is approximate. Data pertain to methanol as the solvent. RO” is more nucleophilic than ROH Alkoxide ion Alcohol f f RCO” is more nucleophilic than RCOH Carboxylate ion Carboxylic acid As long as the nucleophilic atom is the same, the more basic the nucleophile, the more reactive it is. An alkoxide ion (RO ) is more basic and more nucleophilic than a carboxylate ion (RCO; ). o - lo RO is more nucleophilic than RCO Stronger base Weaker base Conjugate acid is ROH: Conjugate acid is RCO,H: K=10 "(pk = 16) K=10 “(pk =5) The comection between basicity and nucleophilicity holds when comparing atoms in the same row of the periodic table. Thus, HO” is more basic and more nucleophilic than Fº, and HN is more basic and more nucleophilic than H,0O. 1t does not hold when proceeding down a column in the periodic table. For example, 1" 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 sol- vated by hydrogen bonds of the type illustrated in Figure 8.4. Smaller anions, because of their high charge-to-size ratio, are more strongly solvated than larger ones. In order to act as a nucleophile, the halide must shed some of the solvent molecules that surround it. Among the halide anions, F” forms the strongest hydrogen bonds to water and alco- hols, and I” the weakest. Thus, the nucleophilicity of F” is suppressed more than that of CI, CI” more than Br, and Br more than T'. Similarly, HO” is smaller, more sol- vated, and less nucleophilic than HS”. Nucleophilicity is also related to polarizability, or the ease of distortion of the elec- Eres nd tron “cloud” surrounding the nucleophile. The partial bond between the nucleophile and a highly polarizable species the alkyl halide that characterizes the Sy2 transition state is more fully developed ata | is soft. lodide is a very soft longer distance when the nucleophile is very polarizable than when it is not. An increased ppssophile. Converse : o fluoride ion is not very polar- degree of bonding to the nucleophile lowers the energy of the transition state and izable and is said to be a hard nucleophile. Forward Main Menul Toe] Study Guide TOC Student OLC MHHE Website 316 FIGURE 8.5 The Sy1 mecha- nism for hydrolysis of tert- butyl bromide. FIGURE 8.6 Energy diagram illustrating the Sy1 mecha- nism for hydrolysis of tert- butyl bromide. E Forward CHAPTER EIGHT | Nucleophilic Substitution The Overall Reaction: (CH)aCBr + 2H0 — (CH);COH + HO! + Br” tert-Butyl bromide Water tert-Butyl alcohol Hydronium ion Bromide ion Step 1: The alkyl halide dissociates to a carbocation and a halide ion. (Hc OB 2 cant + tert-Butyl bromide tert-Butyl cation Bromide ion Step 2: The carbocation formed in step 1 reacts rapidly with a water molecule. Water s a nucleophile. This step completes the nucleophilic substitution stage of the mechanism and yields an alkyloxonium ion. H H / +/ (cre o. E mac N N H H 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. H H H OND - -/ (CHyse O + a — (CHane—O; + H—o, H H H H tert-Butyloxonium ion Water tert-Butyl alcohol Hydronium ion 5 & (CH5)5C-— Br 2H,0 a a (CH)C--- OH, Br. HO Ea . ve (CH5)aC Br.2H,0 a E (CH;):CO —-H-- OH, Br” I H Potential energy — (CH;):CBr, 2H,0 (CH,aCOH,, Br,H,O (CH;)-COH, Br, HO” Reaction coordinate —— Main Menu] TOC] StudyGuide TOC] —StudentOLC| | MHHE Website Back| 8.9 Carbocation Stability and Sy! Reaction Rates Neither formic acid nor water is very nucleophilic, and so Sx2 substitution is suppressed. The relative rates of hydrolysis of a group of alkyl bromides under these conditions are presented in Table 8.5. The relative rate order in Sx1 reactions is exactly the opposite of that seen in Sx2 reactions: Swl reactivity: methyl < primary < secondary < tertiary Sn2 reactivity: tertiary < secondary < primary < methyl Clearly, the steric crowding that influences reaction rates in Sx2 processes plays no role in Sxl reactions. The order of alkyl halide reactivity in Sx1 reactions is the same as the order of carbocation stability: the more stable the carbocation, the more reactive the alkyl halide. We have seen this situation before in the reaction of alcohols with hydrogen halides (Section 4.12), in the acid-catalyzed dehydration of alcohols (Section 5.9), and in the conversion of alkyl halides to alkenes by the El mechanism (Section 5.17). As in these other reactions, an electronic effect, specifically, the stabilization of the carboca- tion intermediate by alkyl substituents, is the decisive factor. PROBLEM 8.9 Identify the compound in each of the following pairs that reacts at the faster rate in an Sy1 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 SAMPLE SOLUTION (a) Isopropyl bromide, (CHs)>CHBr, is a secondary alkyl halide, whereas isobutyl bromide, (CHs)>CHCH>Br, is primary. Since the rate- determining step in an Sy1 reaction is carbocation formation and since secondary carbocations are more stable than primary carbocations, isopropyl bromide is more reactive than isobutyl bromide in nucleophilic substitution by the Sy1 mechanism. Primary carbocations are so high in energy that their intermediacy in nucleophilic substitution reactions is unlikely. When ethyl bromide undergoes hydrolysis in aqueous formic acid, substitution probably takes place by a direct displacement of bromide by water in an Sw2-like process. ENT: Reactivity of Some Alkyl Bromides Toward Substitution by the Sy1 Mechanism* Alkyl bromide Structure Class Relative rate! Methyl bromide CH3Br Unsubstituted 1 Ethyl bromide CHsCH,Br Primary 2 Isopropyl bromide (CH3)>CHBr Secondary 43 tert-Butyl bromide (CH3)3CBr Tertiary 100,000,000 *Solvolysis in aqueous formic acid. *Ratio of rate constant k for indicated alkyl bromide to k for methyl bromide at 25º. Forward Main Menul Toe] Study Guide TOC Student OLC 317 MHHE Website 318 FIGURE 8.7 me O tion of a racemic product by nucleophilic substitution via a carbocation intermediate. Back| Forward Main Menul CHAPTER EIGHT | Nucleophilic Substitution CH; Bimolecular transition state for hydrolysis of ethyl bromide 8.10 STEREOCHEMISTRY OF Sy1 REACTIONS Although Sy2 reactions are stereospecific and proceed with inversion of configuration at carbon, the situation is not as clear-cut for Syl reactions. When the leaving group is attached to the stereogenic center of an optically active halide, ionization gives a carbo- cation intermediate that is achiral. It is achiral because the three bonds to the positively charged carbon lie in the same plane, and this plane is a plane of symmetry for the car- bocation. As shown in Figure 8.7, such a carbocation should react with a nucleophile at the same rate at either of its two faces. We expect the product of substitution by the Syl mechanism to be racemic and optically inactive. This outcome is rarely observed in prac- tice, however. Normally, the product is formed with predominant, but not complete, inversion of configuration. For example, the hydrolysis of optically active 2-bromooctane in the absence of added base follows a first-order rate law, but the resulting 2-octanol is formed with 66% inversion of configuration. cu, H E—oH CH«(CH>)s (CH5)sCH3 — CHs(CH5)s (R)(—)-2-Bromooctane (S)-(+)-2-Octanol (RJ(-)-2-Octanol 66% net inversion corresponds to 83% 8, 17% R 3º. ão 0 e j o o eco , o8o o 50% 50% TOC| Study Guide TOC] StudentOLC| — MHHE Website 8.12 Effect of Solvent on the Rate of Nucleophilic Substitution 321 Relative Rate of Sy1 Solvolysis of tert-Butyl Chloride as a Until tod Function of Solvent Polarity* Solvent Dielectric constant e Relative rate Acetic acid 6 1 Methanol 33 4 Formic acid 58 5,000 Water 78 150,000 *Ratio of first-order rate constant for solvolysis in indicated solvent to that for solvolysis in acetic acid at 25º€. According to the Sx1 mechanism, a molecule of an alkyl halide ionizes to a pos- itively charged carbocation and a negatively charged halide ion in the rate-determining step. As the alkyl halide approaches the transition state for this step, a partial positive charge develops on carbon and a partial negative charge on the halogen. Figure 8.9 con- trasts the behavior of a nonpolar and a polar solvent on the energy of the transition state. Polar and nonpolar solvents are similar in their interaction with the starting alkyl halide, but differ markedly in how they affect the transition state. A solvent with a low dielec- tric constant has little effect on the energy of the transition state, whereas one with a high dielectric constant stabilizes the charge-separated transition state, lowers the acti- vation energy, and increases the rate of reaction. 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. q: 8 ê Energy of alkyl halide Rx is approximately the + Rx € e mn Bb » ó q nonpolar or a polar + FIGURE 8.9 A polar solvent solvent. stabilizes the transition state of an Sn! reaction and Nonpolar solvent Polar solvent increases its rate. Jo E Forward Main Menul Toe] Study Guide TOC) Student OLC| MHHE Website 322 CHAPTER EIGHT | Nucleophilic Substitution Solvent Effects on the Rate of Substitution by the Sy2 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 sol- vents to give a high enough concentration of the nucleophile to allow the reaction to occur at a rapid rate. Other than the requirement that the solvent be polar enough to dis- solve ionic compounds, however, the effect of solvent polarity on the rate of Sy2 reac- tions is small. What is most important is whether or not the polar solvent is protie or aprotic. Water (HOH), alcohols (ROH), and carboxylic acids (RCO,H) are classified as polar protic solvents; they all have OH groups that allow them to form hydrogen bonds to anionic nucleophiles as shown in Figure 8.10. Solvation forces such as these stabilize the anion and suppress its nucleophilicity. Aprotic solvents, on the other hand, lack OH groups and do not solvate anions very strongly, leaving them much more able to express their nucleophilic character. Table 8.7 compares the second-order rate constants k for Sx2 substitution of 1-bromobutane by azide ion (a good nucleophile) in some common polar aprotic solvents with the corresponding k's for the much slower reactions observed in the polar protic solvents methanol and water. CH;CH,CH,CH5Br + N; — CHaCH,CH,CH5N; + Br 1-Bromobutane Azide ion 1-Azidobutane Bromide ion FIGURE 8.10 Hydrogen bonding of the solventto the nucleophile stabilizes the nu- cleophile and makes it less reactive. ENT: Relative Rate of Sn2 Displacement of 1-Bromobutane by Azide in Various Solvents* Structural Dielectric Type of Relative Solvent formula constante solvent rate Methanol CH30H 32.6 Polar protic 1 Water H,0 78.5 Polar protic 7 Dimethyl sulfoxide (CH3))S=O 48.9 Polar aprotic 1300 N,N-Dimethylformamide (CH;))NCH=O 36.7 Polar aprotic 2800 Acetonitrile CH:C=N 37.5 Polar aprotic 5000 *Ratio of second-order rate constant for substitution in indicated solvent to that for substitution in methanol at 25ºC. Back| Forward Main Menul Toe] Study Guide TOC Student OLC MHHE Website 8.13 Substitution and Elimination as Competing Reactions 323 The large rate enhancements observed for bimolecular nucleophilic substitutions in polar aprotic solvents are used to advantage in synthetic applications. An example can be seen in the preparation of alkyl cyanides (nitriles) by the reaction of sodium cyanide with alkyl halides: CHCH,),CH>X + NaCN — CH«CH5)CH>CN + NaX Hexyl halide Sodium cyanide Hexyl 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 by heating with sodium cyanide. Although this is a perfectly acceptable synthetic reaction, a period of over 20 hours was required. Changing the solvent to dimethyl sulfoxide brought about an increase in the reaction rate sufficient to allow the less reactive substrate hexyl chloride to be used instead, and the reaction was complete (91% yield) in only 20 minutes. The rate at which reactions occur can be important in the laboratory, and under- standing 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 it is the nature of the substrate and the nucleophile that, more than anything else, determines what product is formed. 8.13 SUBSTITUTION AND ELIMINATION AS COMPETING REACTIONS We have seen that an alkyl halide and a Lewis base can react together in either a sub- stitution or an elimination reaction. B elimination. See +. H , N —C—c— + yo a L e 0 C— + x nucleophilic sitio 4 Y Substitution can take place by the Sxl or the Sx2 mechanism, elimination by El or E2. How can we predict whether substitution or elimination will be the principal reac- tion observed with a particular combination of reactants? The two most important fac- tors 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 typical secondary alkyl halide such as iso- propyl bromide reacts with a typical nucleophile such as sodium ethoxide mainly by elimination: CHsÇHCH, RE CH;CH=CH, + CHSÇHCH; Br OCH,CH; Isopropyl bromide Propene (87%) Ethyl isopropyl ether (13%) Figure 8.11 illustrates the close relationship between the E2 and Sy2 pathways for this case, and the results cited in the preceding equation clearly show that E2 is faster than Sx2 when the alkyl halide is secondary and the nucleophile is a strong base. E Forward Main Menul Toe] Study Guide TOC) Student OLC| MHHE Website 326 CHAPTER EIGHT | Nucleophilic Substitution 8.14 SULFONATE ESTERS AS SUBSTRATES IN NUCLEOPHILIC SUBSTITUTION Two kinds of starting materials have been examined in nucleophilic substitution reac- tions to this point. In Chapter 4 we saw alcohols can be converted to alkyl halides by reaction with hydrogen halides and pointed out that this process is a nucleophilic sub- stitution taking place on the protonated form of the alcohol, with water serving as the leaving group. In the present chapter the substrates have been alkyl halides, and halide ions have been the leaving groups. A few other classes of organic compounds undergo nucleophilic substitution reactions analogous to those of alkyl halides, the most impor- tant of these being alkyl esters of sulfonic acids. Sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid are strong acids, comparable in acidity with sulfuric acid. Methanesulfonic acid p-Toluenesulfonic acid Alkyl sulfonates are derivatives of sulfonic acids in which the proton of the hydroxyl group is replaced by an alkyl group. They are prepared by treating an alcohol with the appropriate sulfonyl chloride. [ [ rR0+ RiSZea — RO-SR' + HCl J | H o Alcohol Sulfonyl chloride Sulfonate ester Hydrogen chloride These reactions are usually carried out in the presence of pyridine. o o Diciro I CH;CH,0H + CH; je! CH; 0 0 Ethanol p:Toluenesulfonyl Ethyl p-toluenesulfonate chloride (12%) Alkyl sulfonate esters resemble alkyl halides in their ability to undergo elimina- tion and nucleophilic substitution. [ [ a OD — R>Y + co Sen 0 | 0 Nucleophile p:Toluenesulfonate Product of p-Toluenesulfonate ester nucleophilic anion substitution E Forward Main Menul Toe] Study Guide TOC) Student OLC| MHHE Website 8.14 — Sulfonate Esters as Substrates in Nucleophilic Substitution 327 The sulfonate esters used most frequently are the p-toluenesulfonates. They are com- monly known as tosylates and given the abbreviated formula ROTs. H KCN, H —O Ss CH,OTs etantvarr CHEN (3-Cyclopentenylmethyl 4(Cyanomethyleyclo- p-toluenesulfonate pentene (86%) p-Toluenesulfonate (TsO) is a very good leaving group. As Table 8.8 reveals, alkyl p-toluenesulfonates undergo nucleophilic substitution at rates that are even faster than those of alkyl iodides. A correlation of leaving-group abilities with carbon-halogen bond strengths was noted earlier, in Section 8.2. Note also the correlation with the basic- ity of the leaving group. Iodide is the weakest base among the halide anions and is the best leaving group, fluoride the strongest base and the poorest leaving group. A similar correlation with basicity is seen among oxygen-containing leaving groups. The weaker the base, the better the leaving group. Trifluoromethanesulfonic acid (CF;SO,0H) is a Esse maneio much stronger acid than p-toluenesulfonic acid, and therefore trifluoromethanesulfonate esters are called triflates. is a much weaker base than p-toluenesulfonate and a much better leaving group. Notice too that strongly basic leaving groups are absent from Table 8.8. In gen- eral, any species that has a K, less than 1 for its conjugate acid cannot be a leaving group in a nucleophilic substitution. Thus, hydroxide (HO) is far too strong a base to be dis- placed from an alcohol (ROH), and alcohols do not undergo nucleophilic substitution. mM strongly acidic media, alcohols are protonated to give alkyloxonium ions, and these do undergo nucleophilic substitution, because the leaving group is a weakly basic water molecule. Since halides are poorer leaving groups than p-toluenesulfonate, alkyl p-toluene- sulfonates can be converted to alkyl halides by Sy2 reactions involving chloride, bro- mide, or iodide as the nucleophile. CHSÇHCH CH, + NaBr 22, CHÇHCHCH, + NaOTs OTs Br sec-Butyl Sodium sec-Butyl Sodium p-toluenesulfonate bromide bromide (82%) p-toluenesulfonate PENHA: Approximate Relative Leaving-Group Abilities* Conjugateacidof Ka of conjugate Leaving group Relative rate leaving group acid pKa F 108 HF 3.5 x 104 3.5 cl 10º HCl 107 =7 Br 10º HBr 10º -9 I 10? HI 10º —10 HO 10! H0* 55 -1.7 Tso 105 TsOH 6 x 102 -28 CF5S0,0 108 CF;S0,0H 10º -6 *Values are approximate and vary according to substrate. Back| Forward Main Menul Toe] Study Guide TOC Student OLC MHHE Website 328 Back| CHAPTER EIGHT | Nucleophilic Substitution PROBLEM 8.13 Write a chemical equation showing the preparation of octade- cyl p-toluenesulfonate. PROBLEM 8.14 Write equations showing the reaction of octadecyl p-toluene- sulfonate with each of the following reagents: f (a) Potassium acetate (KOCCHs) (b) Potassium iodide (KI) (c) Potassium cyanide (KCN) (d) Potassium hydrogen sulfide (KSH) (e) Sodium butanethiolate (NaSCH>CH>CH>CHs) SAMPLE SOLUTION All these reactions of octadecyl p-toluenesulfonate have been reported in the chemical literature, and all proceed in synthetically useful yield. You should begin by identifying the nucleophile in each of the parts to this problem. The nucleophile replaces the p-toluenesulfonate leaving group in an Sy2 reaction. In part (a) the nucleophile is acetate ion, and the product of nucleophilic substitution is octadecyl acetate. o [Ss | chico” + oSors — CH; COCHCH,),6CHa (CH2)isCH3 Acetateion | Octadecyl tosylate Octadecyl acetate Sulfonate esters are subject to the same limitations as alkyl halides. Competition from elimination needs to be considered when planning a functional group transforma- tion that requires an anionic nucleophile, because tosylates undergo elimination reactions, just as alkyl halides do. An advantage that sulfonate esters have over alkyl halides is that their preparation from alcohols does not involve any of the bonds to carbon. The alcohol oxygen becomes the oxygen that connects the alkyl group to the sulfonyl group. Thus, the configuration of a sulfonate ester is exactly the same as that of the alcohol from which it was pre- pared. If we wish to study the stereochemistry of nucleophilic substitution in an opti- cally active substrate, for example, we know that a tosylate ester will have the same con- figuration and the same optical purity as the alcohol from which it was prepared. CH(CH,)s a pToluenesulfonyi CHACHos 7 A chloride 2 Fem Semi» Fi CH; H;€ HC ($)-(+)-2-Octanol (S)-(+)-1-Methylheptyl p-toluenesulfonate [od +9.9º [aê +7.9º (optically pure) (optically pure) The same cannot be said about reactions with alkyl halides as substrates. The conver- sion of optically active 2-octanol to the corresponding halide does involve a bond to the stereogenic center, and so the optical purity and absolute configuration of the alkyl halide need to be independently established. MainMenu| TOC] Study Guide TOC) StudentOLC| — MHHE Website Back| 8.16 Summary 331 PN BSEAe) Comparison of Sy1 and Sn2 Mechanisms of Nucleophilic Substitution in Alkyl Halides St Sn2 Characteristics of mechanism Two elementary steps: Single step: nu RS) Rate-determining transition state Molecularity Kinetics and rate law Relative reactivity of halide leaving groups Effect of structure on rate Effect of nucleophile on rate Effect of solvent on rate Stereochemistry Potential for rearrangements Step 2: R$“ NU” —> R—Nu lonization of alkyl halide (step 1) is rate-determining. (Section 8.8) Brroncitod (Section 8.8) Unimolecular (Section 8.8) First order: Rate = k[alkyl halide] (Section 8.8) RI> RBr > RCl= RF (Section 8.2) RaCX > RoCHX > RCHX > CHX Rate is governed by stability of car- bocation that is formed in ioniza- tion step. Tertiary alkyl halides can react only by the Sy1 mechanism; they never react by the Sy2 mecha- nism. (Section 8.9) Rate of substitution is independent of both concentration and nature of nucleophile. Nucleophile does not participate until after rate- determining step. (Section 8.8) Rate increases with increasing polarity of solvent as measured by its dielectric constant e. (Section 8.12) Not stereospecific: racemization accompanies inversion when leav- ing group is located at a stereogen- ic center. (Section 8.10) Carbocation intermediate capable of rearrangement. (Section 8.11) Nucleophile displaces leaving group; bonding to the incoming nucleophile accompanies cleavage of'the bond to the leaving group. (Sections 8.3 and 8.5) SoNu--R=—-X:ê (Sections 8.3 and 8.5) Bimolecular (Section 8.3) Second order: Rate = k[alkyl halide][nucleophile] (Section 8.3) RI> RBr >RCI => RF (Section 8.2) CH5X > RCH5X > RoCHX > R$CX Rate is governed by steric effects (crowding in transition state). Methyl and primary alkyl halides can react only by the Sy2 mecha- nism; they never react by the Sy1 mechanism. (Section 8.6) Rate depends on both nature of nucleophile and its concentration. (Sections 8.3 and 8.7) Polar aprotic solvents give fastest rates of substitution; solvation of Nu:” is minimal and nucleophilicity is greatest. (Section 8.12) Stereospecific: 100% inversion of configuration at reaction site. Nucleophile attacks carbon from side opposite bond to leaving group. (Section 8.4) No carbocation intermediate; no rearrangement. Forward Main Menul TOC| | Study Guide TOC Student OLC MHHE Website 332 CHAPTER EIGHT | Nucleophilic Substitution Section 8.13 When nucleophilic substitution is used for synthesis, the competition between substitution and elimination must be favorable. However, the normal reaction of a secondary alkyl halide with a base as strong or stronger than hydroxide is elimination (E2). Substitution by the Sx2 mechanism predominates only when the base is weaker than hydroxide or the alkyl halide is primary. Elimination predominates when tertiary alkyl halides react with any anion. Section 8.14 Nucleophilic substitution can occur with leaving groups other than halide. Alkyl p-toluenesulfonates (tosylates), which are prepared from alcohols by reaction with p-toulenesulfonyl chloride, are often used. 7 ROH +ea( soe, noi Seu, (ROTs) 0 Alcohol p-Toluenesulfonyl chloride Alkyl p-toluenesulfonate (alkyI tosylate) Section 8.15 In its ability to act as a leaving group, p-toluenesulfonate is comparable to iodide. NT pn - Nu: R—OTs —> Nu—R + OTs Nucleophile Alkyl Substitution — p-Toluenesulfonate p-toluenesulfonate product ion The reactions of alcohols with hydrogen halides to give alkyl halides (Chapter 4) are nucleophilic substitution reactions of alkyloxonium ions in which water is the leaving group. Primary alcohols react by an Sx2- like displacement of water from the alkyloxonium ion by halide. Sec- ondary and tertiary alcohols give alkyloxonium ions which form carbo- cations in an Swl-like process. Rearrangements are possible with secondary alcohols, and substitution takes place with predominant, but not complete, inversion of configuration. PROBLEMS 817 Write the structure of the principal organic product to be expected from the reaction of I-bromopropane with each of the following: (a) Sodium iodide in acetone o (b) Sodium acetate crdona) in acetic acid (c) Sodium ethoxide in ethanol (d) Sodium cyanide in dimethyl sulfoxide (e) Sodium azide in aqueous ethanol (f) Sodium hydrogen sulfide in ethanol (g) Sodium methanethiolate (NaSCH;) in ethanol Back| Forward Main Menul Toe] Study Guide TOC Student OLC MHHE Website Back| Problems 818 AI the reactions of I-bromopropane in the preceding problem give the product of nucle- ophilic substitution in high yield. High yields of substitution products are also obtained in all but one of the analogous reactions using 2-bromopropane as the substrate. In one case, however, 2- bromopropane is converted to propene, especially when the reaction is carried out at clevated tem- perature (about 55ºC). Which reactant is most effective in converting 2-bromopropane to propene? 819 Each of the following nucleophilic substitution reactions has been reported in the chemical literature. Many of them involve reactants that are somewhat more complex than those we have dealt with to this point. Nevertheless, you should be able to predict the product by analogy to what you know about nucleophilic substitution in simple systems. l (a) BrCH;COCH,CH; — —s acetone o Í (b) ON (5 cocr O, - - acetic acid NaCN ethanol- water (d) NC AL Sena SOHO, Il (e) CICH,COC(CH;), — (0) CH;CH>0CH>CH;Br acetone- water O, CH nai O To acetone TsOCH$ 90 sa CU OCH; cHo CH,CH,CH,CH,0H (h) 1. TSC, pyridine 2. Lil acetone cH;O 8.20 Each of the reactions shown involves nucleophilic substitution. The product of reaction (a) is an isomer of the product of reaction (b). What kind of isomer? By what mechanism does nucle- ophilic substitution occur? Write the structural formula of the product of each reaction. (a) C(CH3) + SNa — FE e (> ' (b) [Te + (sra —s a 8.21 Arrange the isomers of molecular formula C4HsCI in order of decreasing rate of reaction with sodium iodide in acetone. Forward Main Menul Toe] Study Guide TOC Student OLC 333 MHHE Website 336 CHAPTER EIGHT | Nucleophilic Substitution (a) Devise a method for the preparation of CH;CHsC=CH from sodium acetylide and any necessary organic or inorganic reagents. (b) Given the information that K, for acetylene (HC=CH) is 102º (pk, 26), comment on the scope of this preparative procedure with respect to R in RC=CH. Could you prepare (CH) CHC=CH or (CH;);CC=CH in good yield by this method? 833 Give the structures, including stereochemistry, of compounds A and B in the following sequence of reactions: oH pyridine LiBr cc” + on-4 soa Li, compound A > compound B 834 (a) Suggest a reasonable series of synthetic transformations for converting trans-2-methyl- eyclopentanol to cis-2-methyleyclopentyl acetate. cis-2-Methyleyclopentyl Ii acetate HC 'OCCH; (b) How could you prepare cis-2-methyleyclopentyl acetate from I-methyleyclopentanol? 835 Optically pure (S)-(+)-2-butanol was converted to its methanesulfonate ester according to the reaction shown. cH, CH;SO,CI H oH ——— sec-butyl methanesulfonate pyridine CH,CH; (a) Write the Fischer projection of the sec-butyl methanesulfonate formed in this reaction. (b) The sec-butyl methanesulfonate in part (a) was treated with NaSCH,CH; to give à product having an optical rotation ap of —25º. Write the Fischer projection of this product. By what mechanism is it formed? What is its absolute configuration (Rors)? When treated with PBrs , optically pure ($)-(+)-2-butanol gave 2-bromobutane hav- ing an optical rotation ap = —38º. This bromide was then allowed to react with NaSCH,CH; to give a product having an optical rotation ap of +23º. Write the Fischer projection for (—)-2-bromobutane and specify its configuration as R or S. Does the reaction of 2-butanol with PBr; proceed with predominant inversion or retention of configuration? (o) (d) What is the optical rotation of optically pure 2-bromobutane? 836 Ina classic experiment, Edward Hughes (a colleague of Ingold's at University College, Lon- don) studied the rate of racemization of -iodooctane by sodium iodide in acetone and compared it with the rate of incorporation of radioactive iodine into 2-iodooctane. RI + [13] SS RE +I (1* = radioactive iodine) How will the rate of racemization compare with the rate of incorporation of radioactivity if (a) Each act of exchange proceeds stereospecifically with retention of configuration? (b) Each act of exchange proceeds stereospecifically with inversion of configuration? (c) Each act of exchange proceeds in a stereorandom manner, in which retention and inversion of configuration are equally likely? E Forward Main Menul Toe] Study Guide TOC) Student OLC| MHHE Website Back| Problems 8.37 The ratio of elimination to substitution is exactly the same (26% elimination) for 2-bromo- 2-methylbutane and 2-iodo-2-methylbutane in 80% ethanol/20% water at 25ºC. (a) By what mechanism does substitution most likely occur in these compounds under these conditions? (b) By what mechanism does elimination most likely occur in these compounds under these conditions? (c) Which substrate undergoes substitution faster? (d) Which substrate undergoes elimination faster? (e) What two substitution products are formed from each substrate? (f) What two elimination products are formed from each substrate? (8) Why do you suppose the ratio of elimination to substitution is the same for the two substrates? 838 The reaction of 2,2-dimethyl-1-propanol with HBr is very slow and gives 2-bromo-2-methyl- propane as the major product. cH; cH; cadcou > CHCCH.CHs dm, de Give a mechanistic explanation for these observations. 839 Solvolysis of 2-bromo-2-methylbutane in acetic acid containing potassium acetate gave three products. Identify them. 840 Solvolysis of 1,2-dimethyIpropyl p-toluenesulfonate in acetic acid (75ºC) yields five differ- ent products: three are alkenes and two are substitution products. Suggest reasonable structures for these five products. 841 Solution A was prepared by dissolving potassium acetate in methanol. Solution B was pre- pared by adding potassium methoxide to acetic acid. Reaction of methyl iodide either with solu- tion A or with solution B gave the same major product. Why? What was this product? 842 If the temperature is not kept below 25ºC during the reaction of primary alcohols with p- toluenesulfonyl chloride in pyridine, it is sometimes observed that the isolated product is not the desired alkyl p-toluenesulfonate but is instead the corresponding alkyl chloride. Suggest a mech- anistic explanation for this observation. 843 The reaction of cyclopentyl bromide with sodium cyanide to give cyclopentyl cyanide H NaCN H ——— Br ethanol-water CN Cyclopentyl bromide Cyclopentyl cyanide proceeds faster if a small amount of sodium iodide is added to the reaction mixture. Can you suggest a reasonable mechanism to explain the catalytic function of sodium iodide? 844 Illustrate the stercochemistry associated with unimolecular nucleophilic substitution by con- structing molecular models of cis-4-tert-butylcyclohexyl bromide, its derived carbocation, and the alcohols formed from it by hydrolysis under Sx1 conditions. 845 Given the molecular formula CçH,1Br, construct a molecular model of the isomer that is a primary alkyl bromide yet relatively unreactive toward bimolecular nucleophilic substitution. 337 8 8 Forward Main Menul Toe] Study Guide TOC Student oLe] MHHE Website 338 CHAPTER EIGHT | Nudeophilic Substitution 846 Cyclohexyl bromide is less reactive than noncyclic secondary alkyl halides toward Sw2 sub- itution. Construct a molecular model of cyclohexyl bromide and suggest a reason for its low & 847 1-Bromobicyclo[2.2. I]heptane (the structure of which is shown) is exceedingly unreactive toward nucleophilic substitution by either the Sw1 or Sx2 mechanism. Use molecular models to help you understand why. & Br 1-Bromobicyclo[2.2.1]heptane