Chapter 8 Nucleophilic Substitution Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 1

8.1 Functional Group Transformation By Nucleophilic Substitution

Nucleophilic Substitution Y : – : X – + + R X Y R Nucleophile is a Lewis base (electron-pair donor), often negatively charged and used as Na+ or K+ salt, e.g. NaBr. Substrate is usually an alkyl halide (an sp3 carbon). 2

Nucleophilic Substitution Substrate cannot be an a vinylic halide or an aryl halide, except under certain conditions to be discussed in Chapter 12. In these environments (sp2) it is difficult to displace Xˉ. C X X vinylic halide aryl halide 3

Table 8.1 Examples of Nucleophilic Substitution Alkoxide ion as the nucleophile .. O: R' – + R X gives an ether. + : X R .. O R' – 4

Ethyl isobutyl ether (66%) Example (CH3)2CHCH2ONa + CH3CH2Br Isobutyl alcohol (CH3)2CHCH2OCH2CH3 + NaBr Ethyl isobutyl ether (66%) 5

Table 8.1 Examples of Nucleophilic Substitution Carboxylate ion as the nucleophile O .. – R'C O: + R X .. .. gives an ester. + : X R O R'C – 4

Ethyl octadecanoate (95%) Example O CH3(CH2)16C OK + CH3CH2I acetone, water + KI O CH2CH3 CH3(CH2)16C Ethyl octadecanoate (95%) 7

Table 8.1 Examples of Nucleophilic Substitution Hydrogen sulfide ion as the nucleophile S: – .. H + R X gives a thiol. + : X R .. S H – 4

Example KSH + CH3CH(CH2)6CH3 Br ethanol, water CH3CH(CH2)6CH3 + KBr SH 2-Nonanethiol (74%) CH3CH(CH2)6CH3 SH 9

Table 8.1 Examples of Nucleophilic Substitution Cyanide ion as the nucleophile – C N : + R X gives a nitrile. + : X R – C N : 4

Cyclopentanecarbonitrile (70%) CN + NaBr Example Br NaCN + DMSO Cyclopentanecarbonitrile (70%) CN + NaBr 11

Table 8.1 Examples of Nucleophilic Substitution Azide ion as the nucleophile .. – N : + R X .. gives an alkyl azide. + : X R – N : 4

Example NaN3 + CH3CH2CH2CH2CH2I 2-Propanol-water CH3CH2CH2CH2CH2N3 + NaI Pentyl azide (52%) 13

Table 8.1 Examples of Nucleophilic Substitution Iodide ion as the nucleophile – .. : I + R X gives an alkyl iodide. + : X R – .. I : 4

Example + NaI CH3CHCH3 Br acetone + NaBr CH3CHCH3 I NaI is soluble in acetone; NaCl and NaBr are not soluble in acetone. acetone + NaBr CH3CHCH3 I Isopropyl iodide 63% 16

8.2 Relative Reactivity of Halide Leaving Groups 17

RI most reactive RBr RCl RF least reactive Generalization Reactivity of halide leaving groups in nucleophilic substitution is the same as for elimination (weakest base is the best LG). RI RBr RCl RF most reactive least reactive 18

What is the single organic product obtained ? Problem 8.2 When 1-bromo-3-chloropropane is allowed to react with one molar equivalent of sodium cyanide in aqueous ethanol. What is the single organic product obtained ? BrCH2CH2CH2Cl + NaCN Br is a better leaving group than Cl 19

What is the single organic product obtained ? Problem 8.2 When 1-bromo-3-chloropropane is allowed to react with one molar equivalent of sodium cyanide in aqueous ethanol. What is the single organic product obtained ? BrCH2CH2CH2Cl + NaCN CH2CH2CH2Cl + NaBr C N : 19

8.3 The SN2 Mechanism of Nucleophilic Substitution 17

Second-order kinetics infers a bimolecular rate-determining step Many nucleophilic substitutions follow a second-order rate law. CH3Br + HO –  CH3OH + Br – rate = k[CH3Br][HO – ] Second-order kinetics infers a bimolecular rate-determining step Proposed mechanism is called SN2, which stands for substitution nucleophilic bimolecular 21

Bimolecular Mechanism, SN2 HO CH3 Br  transition state one step HO – CH3Br + HOCH3 Br – 22

This is the Walden inversion. Stereochemistry Nucleophilic substitutions that exhibit second-order kinetic behavior are stereospecific and proceed with inversion of configuration. This is the Walden inversion. 24

Inversion of Configuration Nucleophile attacks carbon from side opposite the bond to the leaving group. Three-dimensional arrangement of bonds in the product is opposite to that of the reactant. 25

Stereospecific Reaction A stereospecific reaction is one in which stereoisomeric starting materials yield products that are stereoisomers of each other. The reaction of 2-bromooctane with NaOH (in ethanol-water) is stereospecific. (+)-2-Bromooctane  (–)-2-Octanol (–)-2-Bromooctane  (+)-2-Octanol 24

Stereospecific Reaction (CH2)5CH3 C H CH3 HO (R)-(–)-2-Octanol C H CH3 Br CH3(CH2)5 NaOH (S)-(+)-2-Bromooctane 25

Problem 8.4 The Fischer projection formula for (+)-2-bromooctane is shown alnog with the Fischer projection of the (–)-2-octanol formed from it by nucleophilic substitution with inversion of configuration. H Br CH3 CH2(CH2)4CH3 HO H CH3 CH2(CH2)4CH3 29

8.4 Steric Effects and SN2 Reaction Rates 17

Crowding at the Reaction Site The rate of nucleophilic substitution by the SN2 mechanism is governed by steric effects. Crowding at the carbon that bears the leaving group slows the rate of bimolecular nucleophilic substitution. 33

Table 8.2 Reactivity Toward Substitution by the SN2 Mechanism RBr + LiI  RI + LiBr Alkyl Class Relative bromide rate CH3Br Methyl 221,000 CH3CH2Br Primary 1,350 (CH3)2CHBr Secondary 1 (CH3)3CBr Tertiary too small to measure 33

Decreasing SN2 Reactivity CH3Br CH3CH2Br (CH3)2CHBr Ball and stick models. (CH3)3CBr 34

Decreasing SN2 Reactivity CH3Br CH3CH2Br (CH3)2CHBr Space filling models. (CH3)3CBr 34

Crowding Adjacent to the Reaction Site The rate of nucleophilic substitution by the SN2 mechanism is governed by steric effects. Crowding at the carbon adjacent to the one that bears the leaving group also slows the rate of bimolecular nucleophilic substitution, but the effect is smaller. 33

Table 8.3 Effect of Chain Branching on Rate of SN2 Substitution RBr + LiI  RI + LiBr Alkyl Structure Relative bromide rate Ethyl CH3CH2Br 1.0 Propyl CH3CH2CH2Br 0.8 Isobutyl (CH3)2CHCH2Br 0.036 Neopentyl (CH3)3CCH2Br 0.00002 35

8.5 Nucleophiles and Nucleophilicity 17

The nucleophiles described in Sections 8.1-8.4 have been anions. .. HO : – CH3O HS C N etc. Not all nucleophiles are anions. Many are neutral. .. HOH CH3OH NH3 : for example All nucleophiles, however, are Lewis bases. 6

Nucleophilicity is a measure of the reactivity of a nucleophile Table 8.4 compares the relative rates of nucleophilic substitution of a variety of nucleophiles toward methyl iodide as the substrate. The standard of comparison is methanol, which is assigned a relative rate of 1.0. 2

Table 8.4 Nucleophilicity Rank Nucleophile Relative rate very good I-, HS-, RS- >105 good Br-, HO-, 104 RO-, CN-, N3- fair NH3, Cl-, F-, RCO2- 103 weak H2O, ROH 1 very weak RCO2H 10-2 5

Table 8.4 Nucleophilicity Rank Nucleophile Relative rate good HO–, RO– 104 fair RCO2– 103 weak H2O, ROH 1 When the attacking atom is the same (oxygen in this case), nucleophilicity increases with increasing basicity. Charged is better than neutral (HO– vs H2O). 7

Major factors that control nucleophilicity Basicity In a horizontal row of the periodic table, nucleophilicity parallels basicity. Solvation Small negative ions are highly solvated in protic solvents. Large negative ions are less solvated. 10

Table 8.4 Nucleophilicity Rank Nucleophile Relative rate Very good I- >105 good Br- 104 fair Cl-, F- 103 A tight solvent shell around an ion makes it less reactive. Larger ions are less solvated than smaller ones and are more nucleophilic. 9

Figure 8.3 Solvation of a chloride ion by ion-dipole attractive forces with water. The negatively charged chloride ion interacts with the positively polarized hydrogens of water. 10

The term solvolysis refers to a nucleophilic Nucleophiles Many of the solvents in which nucleophilic substitutions are carried out are themselves nucleophiles. .. CH3OH .. .. HOH for example The term solvolysis refers to a nucleophilic substitution in which the nucleophile is the solvent. 6

1. Substitution by an anionic nucleophile. Solvolysis 1. Substitution by an anionic nucleophile. R—X + :Nu— R—Nu + :X— 2. Solvolysis. + R—X + :Nu—H R—Nu—H + :X— products of overall reaction: R—Nu + HX 2

Example: Methanolysis Methanolysis is a nucleophilic substitution in which methanol acts as both the solvent and the nucleophile. H O CH3 : H O CH3 : R + –H+ The product is a methyl ether. O : .. CH3 R R—X + 3

Typical solvents in solvolysis solvent product from RX water (HOH) ROH methanol (CH3OH) ROCH3 ethanol (CH3CH2OH) ROCH2CH3 formic acid (HCOH) acetic acid (CH3COH) O O ROCH O O ROCCH3 4

8.6 The SN1 Mechanism of Nucleophilic Substitution 17

Yes. But by a mechanism different from SN2. A question... Tertiary alkyl halides are very unreactive in substitutions that proceed by the SN2 mechanism. Do they undergo nucleophilic substitution at all ? Yes. But by a mechanism different from SN2. The most common examples are seen in solvolysis reactions. 2

Kinetics and Mechanism Some nucleophilic substitutions follow a first-order rate law. rate = k[alkyl halide] First-order kinetics implies a unimolecular rate-determining step. Proposed mechanism is called SN1, which stands for substitution nucleophilic unimolecular 2

Example of a solvolysis. Hydrolysis of tert-butyl bromide. .. + H Br : O C CH3 OH .. C + O : H Br – CH3 13

Example of a solvolysis. Hydrolysis of tert-butyl bromide. .. + O : H C CH3 Br .. C + O : H Br – CH3 This is the nucleophilic substitution stage of the reaction. It involves two steps, loss of Brˉ then attack by water. 13

Example of a solvolysis. Hydrolysis of tert-butyl bromide. The reaction rate is independent of the concentration of the nucleophile and follows a first-order rate law. rate = k[(CH3)3CBr] The first step (slow) begins with ionization of (CH3)3CBr. The mechanism of this step is SN1 rather than SN2. 13

C .. CH3 Br : Mechanism unimolecular slow C H3C CH3 + .. Br – : + 16

Mechanism C H3C CH3 + O : H bimolecular fast C + O : H CH3 17

carbocation formation carbocation capture R+ carbocation formation proton transfer ROH RX ROH2 + 21

Characteristics of the SN1 mechanism first order kinetics: rate = k[RX] unimolecular rate-determining step carbocation intermediate follows carbocation stability rearrangements sometimes observed reaction is not stereospecific much racemization in reactions of optically active alkyl halides 19

8.7 Carbocation Stability and SN1 Reaction Rates 17

Electronic Effects Govern SN1 Rates The rate of nucleophilic substitution by the SN1 mechanism is governed by electronic effects. Carbocation formation is rate-determining. The more stable the carbocation, the faster its rate of formation, and the greater the rate of unimolecular nucleophilic substitution. 33

RBr solvolysis in aqueous formic acid Table 8.5 Reactivity of Some Alkyl Bromides Toward Substitution by the SN1 Mechanism RBr solvolysis in aqueous formic acid Alkyl bromide Class Relative rate CH3Br Methyl 0.6 CH3CH2Br Primary 1.0 (CH3)2CHBr Secondary 26 (CH3)3CBr Tertiary ~100,000,000 33

Decreasing SN1 Reactivity (CH3)3CBr (CH3)2CHBr CH3CH2Br Ball and stick models. CH3Br 34

8.8 Stereochemistry of SN1 Reactions 17

They do not favor preparation of one stereoisomer over another. Generalization Nucleophilic substitutions that exhibit first-order kinetic behavior are not stereospecific. They do not favor preparation of one stereoisomer over another. If stereoisomers are formed they are usually racemic. 24

Stereochemistry of an SN1 Reaction Br CH3(CH2)5 R-(–)-2-Bromooctane (R)-(–)-2-Octanol (17%) H C CH3 OH CH3(CH2)5 HO (CH2)5CH3 (S)-(+)-2-Octanol (83%) H2O 24

Figure 8.6 The Ionization step gives a carbocation and the three bonds to the chiral center become coplanar. If an ion-pair forms, the leaving group shields one face of carbocation and the nucleophile attacks faster at opposite face. If the leaving group dissociates, no shielding occurs and the nucleophile attacks equally at either face. 25

Figure 8.6 25

8.9 Carbocation Rearrangements in SN1 Reactions 17

Because... Carbocations are intermediates in SN1 reactions, therefore, rearrangements are possible. 24

Example CH3 C H CHCH3 Br H2O OH CH2CH3 (93%) CH3 C H CHCH3 + H2O CH3 C 27

8.10 Effect of Solvent on the Rate of Nucleophilic Substitution 17

SN1 Reaction Rates Increase in Polar Solvents In general... SN1 Reaction Rates Increase in Polar Solvents 29

R X  R+ Energy of RX not much affected by polarity of solvent. RX 6

activation energy decreases; transition state stabilized by polar solvent activation energy decreases; rate increases R X  R+ Energy of RX not much affected by polarity of solvent. RX 6

SN2 Reaction Rates Increase in Polar Aprotic Solvents In general... SN2 Reaction Rates Increase in Polar Aprotic Solvents An aprotic solvent is one that can not for hydrogen bonds. 24

Table 8.7 Relative Rate of SN2 Reactivity versus Type of Solvent CH3CH2CH2CH2Br + N3– Solvent Type Relative rate CH3OH polar protic 1 H2O polar protic 7 DMSO polar aprotic 1300 DMF polar aprotic 2800 Acetonitrile polar aprotic 5000 30

Mechanism Summary SN1 and SN2 Primary alkyl halides undergo nucleophilic substitution: they always react by the SN2 mechanism. Tertiary alkyl halides undergo nucleophilic substitution: they always react by the SN1 mechanism. Secondary alkyl halides undergo nucleophilic substitution: they react by the SN1 mechanism in the presence of a weak nucleophile (solvolysis). SN2 mechanism in the presence of a good nucleophile. 1

8.11 Substitution and Elimination as Competing Reactions 17

Two Reaction Types Alkyl halides can react with Lewis bases by nucleophilic substitution and/or elimination. C Y H X : – + -elimination nucleophilic substitution C H X + Y : – 2

Two Reaction Types How can we tell which reaction pathway is followed for a particular alkyl halide? C Y H X : – + -elimination nucleophilic substitution C H X + Y : – 2

Elimination versus Substitution A systematic approach is to choose as a reference point the reaction followed by a typical alkyl halide (secondary) with a typical Lewis base (an alkoxide ion). The major reaction of a secondary alkyl halide with an alkoxide ion is elimination by the E2 mechanism. 2

Example CH3CHCH3 Br NaOCH2CH3 ethanol, 55°C CH3CHCH3 OCH2CH3 CH3CH=CH2 + (87%) (13%) 4

Figure 8.8 E2 CH3CH2 O •• • • – Br 5

5

When is Substitution Favored? Given that the major reaction of a secondary alkyl halide with an alkoxide ion is elimination by the E2 mechanism, we can expect the proportion of substitution to increase with: 1) decreased crowding at the carbon that bears the leaving group 2

Uncrowded Alkyl Halides Decreased crowding at carbon that bears the leaving group increases substitution relative to elimination. primary alkyl halide CH3CH2CH2Br NaOCH2CH3 ethanol, 55°C CH3CH=CH2 + CH3CH2CH2OCH2CH3 (9%) (91%) 8

primary alkyl halide + bulky base But a Crowded Alkoxide Base Can Favor Elimination Even with a Primary Alkyl Halide primary alkyl halide + bulky base CH3(CH2)15CH2CH2Br KOC(CH3)3 tert-butyl alcohol, 40°C + CH3(CH2)15CH2CH2OC(CH3)3 CH3(CH2)15CH=CH2 (87%) (13%) 9

When is Substitution Favored? Given that the major reaction of a secondary alkyl halide with an alkoxide ion is elimination by the E2 mechanism, we can expect the proportion of substitution to increase with: 1) decreased crowding at the carbon that bears the leaving group. 2) decreased basicity of the nucleophile. 2

Weakly Basic Nucleophile Weakly basic nucleophile increases substitution relative to elimination secondary alkyl halide + weakly basic nucleophile KCN CH3CH(CH2)5CH3 Cl pKa (HCN) = 9.1 DMSO (70%) CH3CH(CH2)5CH3 CN 10

Weakly Basic Nucleophile Weakly basic nucleophile increases substitution relative to elimination secondary alkyl halide + weakly basic nucleophile NaN3 pKa (HN3) = 4.6 I (75%) N3 10

Tertiary Alkyl Halides Tertiary alkyl halides are so sterically hindered that elimination is the major reaction with all anionic nucleophiles. Only in solvolysis reactions does substitution predominate over elimination with tertiary alkyl halides. 2

2M sodium ethoxide in ethanol, 25°C 1% 99% (CH3)2CCH2CH3 Br Example CH3CCH2CH3 OCH2CH3 CH3 CH2=CCH2CH3 CH3 CH3C=CHCH3 CH3 + + ethanol, 25°C 64% 36% 2M sodium ethoxide in ethanol, 25°C 1% 99% 12

8.12 Nucleophilic Substitution of Alkyl Sulfonates 17

Leaving Groups We have seen numerous examples of nucleophilic substitution in which X in RX is a halogen. Halogen is not the only possible leaving group, though.

Alkyl methanesulfonate (mesylate) Alkyl p-toluenesulfonate (tosylate) Other RX Compounds ROSCH3 O ROS O CH3 Alkyl methanesulfonate (mesylate) Alkyl p-toluenesulfonate (tosylate) undergo same kinds of reactions as alkyl halides

Preparation Tosylates are prepared by the reaction of alcohols with p-toluenesulfonyl chloride (usually in the presence of pyridine). ROH + CH3 SO2Cl pyridine ROS O CH3 (abbreviated as ROTs)

Tosylates Undergo Typical Nucleophilic Substitution Reactions KCN H CH2OTs H CH2CN (86%) ethanol- water

Table 8.8 Approximate Relative Leaving Group Abilities The best leaving groups are weakly basic. Leaving Relative Conjugate acid pKa of Group Rate of leaving group conj. acid F– 10-5 HF 3.5 Cl– 1 HCl -7 Br– 10 HBr -9 I– 102 HI -10 H2O 101 H3O+ -1.7 TsO– 105 TsOH -2.8 CF3SO2O– 108 CF3SO2OH -6 Sulfonate esters are extremely good leaving groups; sulfonate ions are very weak bases.

Tosylates can be Converted to Alkyl Halides NaBr OTs CH3CHCH2CH3 Br CH3CHCH2CH3 DMSO (82%) Tosylate is a better leaving group than bromide.

Tosylates Allow Control of Stereochemistry Preparation of tosylate does not affect any of the bonds to the chirality center, so configuration and optical purity of tosylate is the same as the alcohol from which it was formed. C H H3C OH CH3(CH2)5 C H H3C OTs CH3(CH2)5 TsCl pyridine

Tosylates Allow Control of Stereochemistry Having a tosylate of known optical purity and absolute configuration then allows the preparation of other compounds of known configuration by SN2 processes. C H CH3 (CH2)5CH3 Nu Nu– SN2 C H H3C OTs CH3(CH2)5

Tosylates also undergo Elimination CH2=CHCH2CH3 NaOCH3 OTs CH3CHCH2CH3 + CH3OH heat CH3CH=CHCH3 E and Z

Secondary Alcohols React with Hydrogen Halides Predominantly with Net Inversion of Configuration H3C Br CH3(CH2)5 CH3 (CH2)5CH3 HBr 87% 13% C H H3C OH CH3(CH2)5

Secondary Alcohols React with Hydrogen Halides with Net Inversion of Configuration H3C Br CH3(CH2)5 CH3 (CH2)5CH3 HBr Most reasonable mechanism is SN1 with front side of carbocation shielded by leaving group. 87% 13% C H H3C OH CH3(CH2)5

Rearrangements can Occur in the Reaction of Alcohols with Hydrogen Halides HBr Br + Br 93% 7%

Rearrangements can Occur in the Reaction of Alcohols with Hydrogen Halides HBr 7% + + 93% Br – Br – Br + Br

End of Chapter 8 Nucleophilic Substitution 17