Chapter 8 I. Nucleophilic Substitution (in( II. Competion with Elimination. Nucleophilic Substitution

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1 hapter 8 I. Nucleophilic Substitution (in( depth) II. ompetion with Elimination Nucleophilic Substitution Substrate is a sp3 hybridized carbon atom (cannot be an a vinylic halide or an aryl halide except under special conditions to be discussed in hem 227) X X Kinetics Bimolecular mechanism Many nucleophilic substitutions follow a second-order rate law. 3 Br Br rate = k [ 3 Br] [ ] What is the reaction order of each starting material? one step What can you infer on a molecular level? concerted What is the overall order of reaction? + 3 Br 3 + Br

2 Bimolecular mechanism Bimolecular mechanism δ 3 transition state δ Br one step one step concerted concerted + 3 Br 3 + Br + 3 Br 3 + Br Generalization Stereochemistry of S N 2 Reactions Nucleophilic substitutions that exhibit second-order kinetic behavior are stereospecific and proceed with inversion of configuration. Inversion of onfiguration Inversion of onfiguration nucleophile attacks carbon from side opposite bond to the leaving group nucleophile attacks carbon from side opposite bond to the leaving group three-dimensional arrangement of bonds in product is opposite to that of reactant

3 Inversion of configuration (Walden inversion) in an SN2 reaction is due to back side attack Roundabout SN2 Mechanism Traditional SN2 Mechanism P.Walden, Berichte, Berichte, 29(1): 29(1): (1896) Riga Polytechnical ollege ould there be another mechanism that provides the same results? SN2 Reaction Mechanisms: Gas Phase (2008) Traditional Physicist Roland Wester and his team in Matthias Weidemüller's group at the University of Freiburg, in Germany, in collaboration with William L. ase's group at Texas Tech University, provide direct evidence for this mechanism in the gas phase. owever, they also detected an additional, unexpected mechanism. In this new pathway, called the roundabout mechanism, chloride bumps into the methyl group and spins the entire methyl iodide molecule 360 before chloride substitution occurs. Videos courtesy of William L. ase, Texas Tech University! Fig. 1. alculated MP2(fc)/EP/aug-cc-pVDZ Born-ppenheimer potential energy along the reaction coordinate g = R-I - R-l for the SN2 reaction l- + 3I and obtained stationary points Roundabout The team imaged SN2 reactions at different collision energies, which depend on the speed at which chloride smashes into methyl iodide. Data at lower collision energies support the traditional SN2 mechanism. owever, at higher collision energies, about 10% of the iodide ions fell outside of the expected distribution. "We saw a group of iodide ions with a much slower velocity than the rest," says Wester. "Since energy is conserved, if iodide ions are slow, the energy has to be somewhere else." n the basis of calculations performed by their colleagues at Texas Tech, the team concluded that the energy missing from the iodide transfers to the methyl chloride product in the form of rotational excitation, supporting the proposed roundabout mechanism. J. Mikosch et al., Science 319, (2008) Published by AAAS Fig. 2. (A to D) enter-of-mass images of the I- reaction product velocity from the reaction of l- with 3I at four different relative collision energies Fig. 3. View of a typical trajectory for the indirect roundabout reaction mechanism at 1.9 ev that proceeds via 3 rotation J. Mikosch et al., Science 319, (2008) J. Mikosch et al., Science 319, (2008) Published by AAAS Published by AAAS

4 Stereospecific Reaction A stereospecific reaction is one in which stereoisomeric starting materials give stereoisomeric products. The reaction of 2-bromooctane with Na (in ethanol-water) is stereospecific. (+)-2-Bromooctane ( )-2-ctanol ( )-2-Bromooctane (+)-2-ctanol 3 ( 2 ) 5 3 Stereospecific Reaction Br Na ( 2 ) (+)-2-Bromooctane ( )-2-ctanol (+)-2-Bromooctane ( )-2-ctanol 3 ( 2 ) 5 Br Question Na ( 2 ) 5 3 1) Draw the Fischer projection formula for (+)-S-2-bromooctane bromooctane. 2) Write the Fischer projection of the ( )-2-octanol formed from it by nucleophilic substitution with inversion of configuration The absolute configurations of (+)-2-bromooctane and ( )-2-( )-2-octanol are respectively: A) R- & R- B) S- and S- ) R- & S- D) S- & R- Br 2 ( 2 ) ( 2 ) 4 3 R- Question True (A) / False (B) A racemic mixture of (R- ) and (S- )-2- bromobutane produces an optically active product. A conceptual view of S N 2 reactions

5 Why does the nucleophile attack from the back side? Steric Effects in S N2 Reactions Reactivity toward substitution by the SN2 mechanism rowding at the Reaction Site The rate of nucleophilic substitution by the SN2 mechanism is governed by steric effects. rowding at the carbon that bears the leaving group slows the rate of bimolecular nucleophilic substitution. RBr + LiI RI + LiBr Alkyl bromide lass Relative rate 3Br Methyl 221,000 32Br Primary 1,350 ( 3)2Br Secondary 1 ( 3)3Br Tertiary too small to measure Decreasing SN2 Reactivity A bulky substituent in the alkyl halide reduces the reactivity of the alkyl halide: steric hindrance 3Br 32Br (3)2Br (3)3Br

6 Decreasing S N 2 Reactivity Reaction coordinate diagrams for (a) the S N 2 reaction of methyl bromide and (b) an S N 2 reaction of a sterically hindered alkyl bromide 3 Br 3 2 Br ( 3 ) 2 Br ( 3 ) 3 Br Question Which chloride will react faster with NaI in acetone? A) B) ) D) rowding Adjacent to the Reaction Site The rate of nucleophilic substitution by the S N 2 mechanism is governed by steric effects. rowding 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. Alkyl bromide Ethyl Effect of chain branching on rate of S N 2 substitution Propyl Isobutyl Neopentyl RBr + LiI RI + LiBr Structure 3 2 Br Br 0.8 Relative rate ( 3 ) 2 2 Br ( 3 ) 3 2 Br Question Which alkyl chloride will react faster with NaI in acetone? A) B) ) D)

7 Nucleophilic Substitution 8.1 Functional Group Transformation By Nucleophilic Substitution Y : + R X Y R + : X nucleophile is a Lewis base (electron-pair donor) often negatively charged and used as Na + or K + salt substrate is usually an alkyl halide, (most often 1 o ) Nucleophiles The nucleophiles described in Sections are anions. : S: 3 : : N : N 3 But, all nucleophiles (neutral electron rich molecules) are Lewis bases. Table 8.1 Examples of Nucleophilic Substitution Alkoxide ion as the nucleophile R'.Ọ: + R X 3 : N 3 gives an ether R'.ỌȮ. R + : X Table 8.1 Examples of Nucleophilic Substitution arboxylate ion as the nucleophile R'.Ọ: + R X Table 8.1 Examples of Nucleophilic Substitution ydrogen sulfide ion as the nucleophile.ṣs: + R X gives an ester R'.ỌȮ. R + : X gives a thiol Ṡ. R + : X

8 Question Question Select the major organic product when (S)-2-( propanol is reacted with Sl 2 in pyridine followed by the addition of NaS in ethanol. A) B) ) D) The best combination of reactants for preparing ( 3 ) S 3 3 is: A) ( 3 ) l SK B) ( 3 ) Br SNa ) ( 3 ) SK D) ( 3 ) SNa Br Table 8.1 Examples of Nucleophilic Substitution yanide ion as the nucleophile : N : + R X Table 8.1 Examples of Nucleophilic Substitution Azide ion as the nucleophile : + N N N: + R X gives a nitrile : N R + : X gives an alkyl azide : N N + N R + : X Generalization 8.2 Relative Reactivity of alide Leaving Groups Reactivity of halide leaving groups in nucleophilic substitution is the same as for elimination. RI RBr most reactive Rl RF least reactive

9 Problem 8.2 Br l + NaN Problem 8.2 A single organic product was obtained when 1-bromo bromo-3-chloropropane was allowed to react with one molar equivalent of sodium cyanide in aqueous ethanol. What was this product? A single organic product was obtained when 1-bromo bromo-3-chloropropane was allowed to react with one molar equivalent of sodium cyanide in aqueous ethanol. What was this product? Br l + NaN Br is a better leaving group than l :N l + NaBr Question What is the major product of the reaction of the dihalide at the right with 1 equivalent of NaS in dimethyl sulfoxide? 8.12 Improved Leaving Groups Alkyl Sulfonates A) B) ) D) Leaving Groups We have seen numerous examples of nucleophilic substitution in which X in RX R is a halogen. RS 3 ther RX ompounds RS 3 alogen is not the only possible leaving group, though. Alkyl Alkyl methanesulfonate p-toluenesulfonate (mesylate) (tosylate) (triflate = -F 3 ) Behave in the same way as alkyl halides

10 Preparation Tosylates are prepared by the reaction of alcohols with p-toluenesulfonyl chloride (usually in the presence of pyridine). Tosylates Undergo Typical Nucleophilic Substitution Reactions KN R + 3 S 2 l pyridine 2 Ts ethanol- water (86%) 2 N RS 3 (abbreviated as RTs) Table 8.8 Approximate Relative Reactivity of Leaving Groups Leaving Group Relative Rate onjugate acid of leaving group pk a of conj. acid The best leaving groups are weakly basic. F 10 F 3.5 l 1 l -7 Br 10 Br -9 I 10 2 I Ts 10 5 Ts -2.8 F 3 S F 3 S 2-6 Table 8.8 Approximate Relative Reactivity of Leaving Groups Tosylates can be onverted to Alkyl alides Leaving Group Relative Rate onjugate acid of leaving group pk a of conj. acid F 10 F 3.5 l 1 l -7 Br 10 Br -9 I 10 2 I Ts 10 5 Ts -2.8 F 3 S F 3 S 2-6 Sulfonate esters are extremely good leaving groups; sulfonate ions are very weak bases Ts NaBr DMS Br (82%) Tosylate is a better leaving group than bromide.

11 Tosylates Allow ontrol 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. Tosylates Allow ontrol of Stereochemistry aving a tosylate of known optical purity and absolute configuration then allows the preparation of other compounds of known configuration by S N 2 processes. 3 ( 2 ) 5 3 Tsl pyridine 3 ( 2 ) 5 3 Ts 3 ( 2 ) 5 3 Ts Nu S N 2 Nu 3 ( 2 ) 5 3 Nucleophiles and Nucleophilicity Rank strong good fair weak very weak Table 8.4 Nucleophilicity Nucleophile Relative rate I -, S -, RS - >10 5 Br -, -, 10 4 R -, N -, N - 3 N 3, l -, F -, R , R 1 R 2 10 Table 8.4 Nucleophilicity Rank Nucleophile Relative rate good fair weak, R 10 4 R , R 1 Nucleophiles and Nucleophilicity S N 1 vs. S N 2 When the attacking atom is the same (oxygen in this case), nucleophilicity increases with increasing basicity.

12 Many of the protic solvents in which nucleophilic substitutions can be carried out are themselves nucleophiles. Nucleophiles 3 and Et for example Solvolysis The term solvolysis refers to a nucleophilic substitution in which the nucleophile is the solvent. An aprotic solvent is one that does not have an group. S N 1 Reactions are favored in Polar Protic Solvents Substitution by an anionic nucleophile: S N 2 kinetics R X + :Nu Solvolysis: S N 1 kinetics R X + :Nu Solvolysis arbocation intemediate R Nu + :X + R Nu + :X 2nd intermediate S N 2 Reactions are favored in Polar Aprotic Non-nucleophilic nucleophilic Solvents Substitution by an anionic nucleophile in an aprotic non-nucleophilic nucleophilic solvent S N 2 kinetics R X + :Nu R Nu + :X Solvolysis (protic solvents) : S N 1 kinetics R X + :Nu Solvolysis + R Nu + :X products of overall reaction R Nu + X Methanolysis is a nucleophilic substitution in which methanol acts as both the solvent and the nucleophile. R X + : : 3 Example: Methanolysis 3 R + : + R : 3 The product is a methyl ether. solvent Some typical solvents in solvolysis water () methanol ( 3 ) ethanol ( 3 2 ) formic acid () acetic acid ( 3 ) product from RX R R 3 R 2 3 R R 3

13 Question Which of the following is not a good nucleophile in an S N 1 solvolysis reaction? A) Na 3 B) 3 ) 3 2 D) 2