8.4 Stereochemistry of SN2 Reactions ts point of attachment to carbon. For this reason, the SN2 mechanism is sometimes referred to as a direct displacement process. The SN2 mechanism for the hydrolysis of methyl bromide may be represented by a single elementary step HO: t CH3 Br HO---CH3---Br:-HOCH3 : Br Hydroxide Methyl Transition Methyl Carbon is partially bonded to both the incoming nucleophile and the departing halide at the transition state. Progress is made toward the transition state as the nucleophile begins to share a pair of its electrons with carbon and the halide ion leaves, taking with it the pair of electrons in its bond to carbon PROBLEM 8.3 Is the two-step sequence depicted in the following equations con- sistent with the second-order kinetic behavior observed for the hydrolysis of methyl bromide? CH3+ HO CH3OH The SN2 mechanism is believed to describe most substitutions in which simple pri mary and secondary alkyl halides react with anionic nucleophiles. All the examples cited in Table 8. 1 proceed by the Sn2 mechanism (or a mechanism very much like SN2- remember, mechanisms can never be established with certainty but represent only our best present explanations of experimental observations). We'll examine the SN2 mecha- nism, particularly the structure of the transition state, in more detail in Section 8.5 after first looking at some stereochemical studies carried out by Hughes and Ingold. 8.4 STEREOCHEMISTRY OF SN2 REACTIONS What is the structure of the transition state in an SN2 reaction? In particular, what is the spatial arrangement of the nucleophile in relation to the leaving group as reactants pass through the transition state on their way to products? Two stereochemical possibilities present themselves. In the pathway shown in Fig ure &la, the nucleophile simply assumes the position occupied by the leaving group. It attacks the substrate at the same face from which the leaving group departs. This is called front-side displacement, or substitution with retention of configuration In a second possibility, illustrated in Figure 8.1b, the nucleophile attacks the sub strate from the side opposite the bond to the leaving group. This is called"back-side dis placement, "or substitution with inversion of configuration. Which of these two opposite stereochemical possibilities operates was determined in experiments with optically active alkyl halides. In one such experiment, Hughes and Ingold determined that the reaction of 2-bromooctane with hydroxide ion gave 2-octanol having a configuration opposite that of the starting alkyl halid ample have opposite config. CH3(CH,)5 (CH2)5CH3 NaOH opposite signs of rotation, it →>HO CH halide/alcohol pairs. (See Sec. tion 7.5) (S)-(+)-2-Bromooctane (R)-(-)-2-Octanol Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
8.4 Stereochemistry of SN2 Reactions 307 its point of attachment to carbon. For this reason, the SN2 mechanism is sometimes referred to as a direct displacement process. The SN2 mechanism for the hydrolysis of methyl bromide may be represented by a single elementary step: Carbon is partially bonded to both the incoming nucleophile and the departing halide at the transition state. Progress is made toward the transition state as the nucleophile begins to share a pair of its electrons with carbon and the halide ion leaves, taking with it the pair of electrons in its bond to carbon. PROBLEM 8.3 Is the two-step sequence depicted in the following equations consistent with the second-order kinetic behavior observed for the hydrolysis of methyl bromide? The SN2 mechanism is believed to describe most substitutions in which simple primary and secondary alkyl halides react with anionic nucleophiles. All the examples cited in Table 8.1 proceed by the SN2 mechanism (or a mechanism very much like SN2— remember, mechanisms can never be established with certainty but represent only our best present explanations of experimental observations). We’ll examine the SN2 mechanism, particularly the structure of the transition state, in more detail in Section 8.5 after first looking at some stereochemical studies carried out by Hughes and Ingold. 8.4 STEREOCHEMISTRY OF SN2 REACTIONS What is the structure of the transition state in an SN2 reaction? In particular, what is the spatial arrangement of the nucleophile in relation to the leaving group as reactants pass through the transition state on their way to products? Two stereochemical possibilities present themselves. In the pathway shown in Figure 8.1a, the nucleophile simply assumes the position occupied by the leaving group. It attacks the substrate at the same face from which the leaving group departs. This is called “front-side displacement,” or substitution with retention of configuration. In a second possibility, illustrated in Figure 8.1b, the nucleophile attacks the substrate from the side opposite the bond to the leaving group. This is called “back-side displacement,” or substitution with inversion of configuration. Which of these two opposite stereochemical possibilities operates was determined in experiments with optically active alkyl halides. In one such experiment, Hughes and Ingold determined that the reaction of 2-bromooctane with hydroxide ion gave 2-octanol having a configuration opposite that of the starting alkyl halide. (S)-()-2-Bromooctane C H H3C CH3(CH2)5 Br (R)-()-2-Octanol H CH3 (CH2)5CH3 HO C NaOH ethanol-water CH3Br CH3 Br slow CH3 HO CH3OH fast Hydroxide ion HO Methyl bromide CH3Br Transition state HO CH3 Br Bromide ion Br Methyl alcohol HOCH3 Although the alkyl halide and alcohol given in this example have opposite configurations when they have opposite signs of rotation, it cannot be assumed that this will be true for all alkyl halide/alcohol pairs. (See Section 7.5) Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTER EIGHT Nucleophilic Substitution FIGURE 8.1 Two contrasting ubstitution of a leaving group(red) by a nucleophile blue). In(a)the nucleophile attacks carbon at the same side from which the leaving group departs In(b)nucle ophilic attack occurs at the (a) Nucleophilic substitution with retention of configuration side opposite the bond to the leaving group. (b)Nucleophilic substitution with inversion of configuration Nucleophilic substitution had occurred with inversion of configuration, consistent with the following transition state CH3(CH,)s H HO PROBLEM 8.4 The Fischer projection formula for (+)-2-bromooctane is shown For a ch Write the Fischer projection of the (-)-2-octanol formed from it by nucleophilic with molecu. substitution with inversion of configuration structura H CH2( CH2)4CH3 PROBLEM 8.5 Would you expect the 2-octanol formed by sn2 hydrolysis of (-) tion and sign of rotation? What about the 2-octanol formed by hydrolysis of racemic 2-brom Numerous similar experiments have demonstrated the generality of this observation. Substitution by the SN2 mechanism is stereospecific and proceeds with inversion of con The first example of a stereo. figuration at the carbon that bears the leaving group. There is a stereoelectronic require- electronic effect in this text ment for the nucleophile to approach carbon from the side opposite the bond to the leav. concerned anti elimination ing group. Organic chemists often speak of this as a Walden inversion, after the German E2 reactions of alkyl halides(Section 5. 16) heist Paul Walden, who described the earliest experiments in this area in the 1890 8.5 HOW SN2 REACTIONS OCCUR When we consider the overall reaction stereochemistry along with the kinetic data, a fairly complete picture of the bonding changes that take place during SN2 reactions merges. The potential energy diagram of Figure 8.2 for the hydrolysis of (S)-(+)-2- ctane is one that is consistent with the experimental observations Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
Nucleophilic substitution had occurred with inversion of configuration, consistent with the following transition state: PROBLEM 8.4 The Fischer projection formula for ()-2-bromooctane is shown. Write the Fischer projection of the ()-2-octanol formed from it by nucleophilic substitution with inversion of configuration. PROBLEM 8.5 Would you expect the 2-octanol formed by SN2 hydrolysis of ()- 2-bromooctane to be optically active? If so, what will be its absolute configuration and sign of rotation? What about the 2-octanol formed by hydrolysis of racemic 2-bromooctane? Numerous similar experiments have demonstrated the generality of this observation. Substitution by the SN2 mechanism is stereospecific and proceeds with inversion of con- figuration at the carbon that bears the leaving group. There is a stereoelectronic requirement for the nucleophile to approach carbon from the side opposite the bond to the leaving group. Organic chemists often speak of this as a Walden inversion, after the German chemist Paul Walden, who described the earliest experiments in this area in the 1890s. 8.5 HOW SN2 REACTIONS OCCUR When we consider the overall reaction stereochemistry along with the kinetic data, a fairly complete picture of the bonding changes that take place during SN2 reactions emerges. The potential energy diagram of Figure 8.2 for the hydrolysis of (S)-()-2- bromooctane is one that is consistent with the experimental observations. CH3 H Br CH2(CH2)4CH3 C CH3(CH2)5 H HO Br CH3 308 CHAPTER EIGHT Nucleophilic Substitution (a) Nucleophilic substitution with retention of configuration (b) Nucleophilic substitution with inversion of configuration The first example of a stereoelectronic effect in this text concerned anti elimination in E2 reactions of alkyl halides (Section 5.16). For a change of pace, try doing Problem 8.4 with molecular models instead of making structural drawings. FIGURE 8.1 Two contrasting stereochemical pathways for substitution of a leaving group (red) by a nucleophile (blue). In (a) the nucleophile attacks carbon at the same side from which the leaving group departs. In (b) nucleophilic attack occurs at the side opposite the bond to the leaving group. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
8.5 HOw SN2 Reactions Occur CH3(CH2)5 FIGURE 8.2 Hyb coordinate Bonding is we between carbon and changes that take 2 CH3(CH,)5 H Ormond Br (CH,)s CH3 C(sP)-Bro bond Hydroxide ion acts as a nucleophile, using an unshared electron pair to attack car bon from the side opposite the bond to the leaving group. The hybridization of the car- bon at which substitution occurs changes from sp' in the alkyl halide to sp- in the tran sition state. Both the nucleophile(hydroxide) and the leaving group(bromide)are partially bonded to this carbon in the transition state. We say that the Sn2 transition state is pentacoordinate; carbon is fully bonded to three substituents and partially bonded to both the leaving group and the incoming nucleophile. The bonds to the nucleophile and the leaving group are relatively long and weak at the transition state Once past the transition state, the leaving group is expelled and carbon becomes tetracoordinate, its hybridization returning to sp' During the passage of starting materials to products, three interdependent and syn- chronous changes take place 1. Stretching, then breaking, of the bond to the leaving group 2. Formation of a bond to the nucleophile from the opposite side of the bond that is 3. Stereochemical inversion of the tetrahedral arrangement of bonds to the carbon at hich substitution occurs Although this mechanistic picture developed from experiments involving optically active alkyl halides, chemists speak even of methyl bromide as undergoing nucleophilic substitution with inversion. By this they mean that tetrahedral inversion of the bonds to carbon occurs as the reactant proceeds to the product HH HO---C see Learning By Hydroxide Met Transition state Methyl Bromide Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
8.5 How SN2 Reactions Occur 309 Hydroxide ion acts as a nucleophile, using an unshared electron pair to attack carbon from the side opposite the bond to the leaving group. The hybridization of the carbon at which substitution occurs changes from sp3 in the alkyl halide to sp2 in the transition state. Both the nucleophile (hydroxide) and the leaving group (bromide) are partially bonded to this carbon in the transition state. We say that the SN2 transition state is pentacoordinate; carbon is fully bonded to three substituents and partially bonded to both the leaving group and the incoming nucleophile. The bonds to the nucleophile and the leaving group are relatively long and weak at the transition state. Once past the transition state, the leaving group is expelled and carbon becomes tetracoordinate, its hybridization returning to sp3 . During the passage of starting materials to products, three interdependent and synchronous changes take place: 1. Stretching, then breaking, of the bond to the leaving group 2. Formation of a bond to the nucleophile from the opposite side of the bond that is broken 3. Stereochemical inversion of the tetrahedral arrangement of bonds to the carbon at which substitution occurs Although this mechanistic picture developed from experiments involving optically active alkyl halides, chemists speak even of methyl bromide as undergoing nucleophilic substitution with inversion. By this they mean that tetrahedral inversion of the bonds to carbon occurs as the reactant proceeds to the product. Hydroxide ion HO Methyl bromide C H H H Br Transition state HO C Br H H H Bromide ion Br Methyl alcohol H H H HO C Potential energy Pentacoordinate carbon is sp2 - hybridized Bonding is weak between carbon and bromine and carbon and oxygen in the transition state Reaction coordinate CH3 (CH2)5 CH3 (CH2)5 CH3 CH3 CH3 Br (CH2)5 CH3 Br H H H C C HO C HO Br HO C(sp O bond σ 3 ) C(sp Br bond σ 3 ) δ δ FIGURE 8.2 Hybrid orbital description of the bonding changes that take place at carbon during nucleophilic substitution by the SN2 mechanism. For an animation of this SN2 reaction, see Learning By Modeling. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
310 CHAPTER EIGHT Nucleophilic Substitution We saw in Section 8.2 that the rate of nucleophilic substitution depends strongly on the leaving group--alkyl iodides are the most reactive, alkyl fluorides the least. In the next section, we'll see that the structure of the alkyl group can have an even greater effec 8.6 STERIC EFFECTS IN SN2 REACTIONS There are very large differences in the rates at which the various kinds of alkyl halides- methyl, primary, secondary, or tertiary--undergo nucleophilic substitution. As Table 8.2 shows for the reaction of a series of alkyl bromides Br Alkyl bromide Lithium iodide Alkyl iodide Lithium bromide the rates of nucleophilic substitution of a series of alkyl bromides differ by a factor of over 10 when comparing the most reactive member of the group(methyl bromide) and the least reactive member (tert-butyl bromide) The large rate difference between methyl, ethyl, isopropyl, and tert-butyl bromides reflects the steric hindrance each offers to nucleophilic attack. The nucleophile must approach the alkyl halide from the side opposite the bond to the leaving group, and, as illustrated in Figure 8.3, this approach is hindered by alkyl substituents on the carbon that is being attacked. The three hydrogens of methyl bromide offer little resistance to approach of the nucleophile, and a rapid reaction occurs. Replacing one of the hydro- gens by a methyl group somewhat shields the carbon from attack by the nucleophile and causes ethyl bromide to be less reactive than methyl bromide. Replacing all three hydro- gen substituents by methyl groups almost completely blocks back-side approach to the tertiary carbon of (CH3)3CBr and shuts down bimolecular nucleophilic substitution. In general, SN2 reactions exhibit the following dependence of rate on substrate structure ncreasing rate of substitution by the sn2 mechanism R3 CX R,cHX RCHoX CHaX Tertiary Least reactive Most reactive most crowded least crowded TABLE 8.2 Reactivity of Some Alkyl Bromides Toward Substitution by the SN2 Mechanism* Alkyl bromide Structure Class Relative ratet Methyl bromid Unsubstituted 221,00 Ethyl bromide CH3 CH2 Br 1,350 Isopropyl bromide (CH3)2CHBr econdary tert-Butyl bromide (CH3)3CBr Too small to measure *Substitution of bromide by lithium iodide in TRatio of second-order rate constant k for indicated alkyl bromide to k for isopropyl bromide at 25C. Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
We saw in Section 8.2 that the rate of nucleophilic substitution depends strongly on the leaving group—alkyl iodides are the most reactive, alkyl fluorides the least. In the next section, we’ll see that the structure of the alkyl group can have an even greater effect. 8.6 STERIC EFFECTS IN SN2 REACTIONS There are very large differences in the rates at which the various kinds of alkyl halides— methyl, primary, secondary, or tertiary—undergo nucleophilic substitution. As Table 8.2 shows for the reaction of a series of alkyl bromides: the rates of nucleophilic substitution of a series of alkyl bromides differ by a factor of over 106 when comparing the most reactive member of the group (methyl bromide) and the least reactive member (tert-butyl bromide). The large rate difference between methyl, ethyl, isopropyl, and tert-butyl bromides reflects the steric hindrance each offers to nucleophilic attack. The nucleophile must approach the alkyl halide from the side opposite the bond to the leaving group, and, as illustrated in Figure 8.3, this approach is hindered by alkyl substituents on the carbon that is being attacked. The three hydrogens of methyl bromide offer little resistance to approach of the nucleophile, and a rapid reaction occurs. Replacing one of the hydrogens by a methyl group somewhat shields the carbon from attack by the nucleophile and causes ethyl bromide to be less reactive than methyl bromide. Replacing all three hydrogen substituents by methyl groups almost completely blocks back-side approach to the tertiary carbon of (CH3)3CBr and shuts down bimolecular nucleophilic substitution. In general, SN2 reactions exhibit the following dependence of rate on substrate structure: Least reactive, most crowded Most reactive, least crowded Tertiary R3CX Secondary R2CHX Primary RCH2X Methyl CH3X Increasing rate of substitution by the SN2 mechanism Alkyl bromide RBr Lithium iodide LiI Lithium bromide LiBr Alkyl iodide RI acetone 310 CHAPTER EIGHT Nucleophilic Substitution TABLE 8.2 Reactivity of Some Alkyl Bromides Toward Substitution by the SN2 Mechanism* Alkyl bromide Methyl bromide Ethyl bromide Isopropyl bromide tert-Butyl bromide CH3Br CH3CH2Br (CH3)2CHBr (CH3)3CBr Structure Unsubstituted Primary Secondary Tertiary Class 221,000 1,350 1 Too small to measure Relative rate† *Substitution of bromide by lithium iodide in acetone. † Ratio of second-order rate constant k for indicated alkyl bromide to k for isopropyl bromide at 25°C. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
8.6 Steric Effects in SN2 Reactions Least crowded- most reactive ea° CH3 Br CH3, Br (CH3)CHBr 666 FIGURE 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 ucleophile 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 SN2 mechanism. 1-Chlorohexane is more reactive CH3CH2 CH2 CH2 CH2 CH2 CI 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 SN2 reaction. Compare the rates of nucleophilic substitution in the series of primary alkyl bromides shown in Table 8.3. Taking ethyl bromide as the tandard 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 [(CH3)3CCH2Br], we see the unusual case of a primary alkyl halide that is practically inert to substitution by the sN2 mechanism because of steric hindrance Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
8.6 Steric Effects in SN2 Reactions 311 PROBLEM 8.6 Identify the compound in each of the following pairs that reacts with sodium iodide in acetone at the faster rate: (a) 1-Chlorohexane or cyclohexyl chloride (b) 1-Bromopentane or 3-bromopentane (c) 2-Chloropentane or 2-fluoropentane (d) 2-Bromo-2-methylhexane or 2-bromo-5-methylhexane (e) 2-Bromopropane or 1-bromodecane SAMPLE SOLUTION (a) Compare the structures of the two chlorides. 1-Chlorohexane is a primary alkyl chloride; cyclohexyl chloride is secondary. Primary alkyl halides are less crowded at the site of substitution than secondary ones and react faster in substitution by the SN2 mechanism. 1-Chlorohexane is more reactive. Alkyl groups at the carbon atom adjacent to the point of nucleophilic attack also decrease the rate of the SN2 reaction. Compare the rates of nucleophilic substitution in the series of primary alkyl bromides shown in Table 8.3. Taking ethyl bromide as the standard and successively replacing its C-2 hydrogens by methyl groups, we see that each additional methyl group decreases the rate of displacement of bromide by iodide. The effect is slightly smaller than for alkyl groups that are attached directly to the carbon that bears the leaving group, but it is still substantial. When C-2 is completely substituted by methyl groups, as it is in neopentyl bromide [(CH3)3CCH2Br], we see the unusual case of a primary alkyl halide that is practically inert to substitution by the SN2 mechanism because of steric hindrance. Cyclohexyl chloride (secondary, less reactive) H Cl 1-Chlorohexane (primary, more reactive) CH3CH2CH2CH2CH2CH2Cl Least crowded– most reactive Most crowded– least reactive CH3Br CH3CH2Br (CH3)2CHBr (CH3)3CBr FIGURE 8.3 Ball-and-spoke and space-filling models of alkyl bromides, showing how substituents shield the carbon atom that bears the leaving group from attack by a nucleophile. The nucleophile must attack from the side opposite the bond to the leaving group. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website