Walden discovered a series of reactions that could interconvert (-)-malic acid and (+)-malic acid.

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1 Chapter 11: Reactions of alkyl halides: nucleophilic substitutions and eliminations Alkyl halides are polarized in the C-X bond, making carbon δ+ (electrophilic). A nucleophilecan attack this carbon, displacing a halide ion (substitution). Inversion of stereochemistry Walden discovered a series of reactions that could interconvert (-)-malic acid and (+)-malic acid. Alternatively, a base can attack an H one carbon away from the C-X bond, forming a double bond and displacing a halide ion (elimination). This chapter will involve the specifics of these reactions, and the two mechanisms that eachreaction can undergo. It was later confirmed that a certain type of nucleophilic substitution reaction will cause the inversion configuration at a chirality center. ch11 Page 1 ch11 Page 2

2 11.2 The S N 2 reaction Let's investigate the kinetics of the reaction of hydroxide with methyl bromide: 11.3 Characteristics of the S N 2 reaction Because the nucleophile must approach from behind (the leaving group takes up the other side) -configuration is invertedwhen the electrophilic carbon is a chirality center. Doubling the concentration of OH - ordoubling the concentration of CH 3 Br will double the reaction rate. The rate equation is Rate = Since concentrations of both reactantsinfluence the rate, they must both be involved in the rate-determining step. The nucleophile attacks and simultaneouslythe leaving group leaves in a concerted reaction. Changing energy of the reactant vs the transition state have different effects on the reaction's rate: Substitution Nucleophilic 2nd-order ch11 Page 3 ch11 Page 4

3 Substrate effects The substrateis the compound that contains the electrophilic carbon and the leaving group. Additional alkyl groups on the electrophilic carbon in the substrate make it more difficult for the nucleophile to approach (this is known as steric hindrance.) Nucleophile effects The nucleophileis the substance with a pair of electrons that attacks the electrophilic carbon. Nucleophiles are usually negative (forming a neutral product) but can be neutral (forming a positive product). Nucleophile strength can be estimated this way: Strong bases are also strong nucleophiles (as long as they're not too branched). RO -, R n N -, R n C - Weak bases can be strong nucleophiles if they're polarizable(electron cloud is large and mobile). RS -, Cl -, Br -, and I - are non-basic nucleophiles. A concentrated (no resonance) anion will be a stronger nucleophile than a neutral species. (This is actually a transition state rate effect -a crowded transition state is too high in energy) Strong nucleophiles are higher energy reactants-this reduces activation energy and makes the reaction faster. ch11 Page 5 ch11 Page 6

4 Leaving group effects The leaving groupis the group that was originally attached to the electrophilic carbon, but is released as the carbon is being attacked. The leaving group becomes more negative. Neutral leaving groups make negative products. Positive leaving groups make neutral products. A good leaving group can stabilize the negative charge. (This reduces transition state energy). Strong bases (OH -, OR -, NH 2- ) make badleaving groups. Solvent effects Protic solventscontain an -OH or -NH group. These electropositive hydrogens will stabilize a nucleophile through hydrogen-bonding. This will lower reactant energy and slow reaction rate. Polar aprotic solventsdo not have H-bonding and will therefore leave the nucleophile more available for attack. Acetone, DMSO, DMF, CH 3 CN, and ethers are common. Make an alcohol into a tosylate to make it a better leaving group. ch11 Page 7 ch11 Page 8

5 Summary of S N 2 effects 11.4 The S N1 reaction A different substitution mechanism happens when there's a hindered substrate, a poor nucleophile, and a protic solvent. The mechanism now has two steps, and only the substrate concentration determines the mechanism -not the nucleophile! Rate = It's Substitution Nucleophic 1st-order ch11 Page 9 ch11 Page 10

6 The S N 1 mechanism 11.5 Characteristics of the S N1 reaction Stabilization of the carbocation intermediate is the most important consideration for the S N 1 reaction: Allylic and benzylic carbocations have resonance stabilization. The carbocation intermediate is flat and can be attacked from either side by the nucleophile. The nucleophile is not important. Acidic reactants even work well! ch11 Page 11 ch11 Page 12

7 Solvent effects 11.7 Elimination reactions of alkyl halides: Zaitsev's rule Protic solventsare able to solvate and stabilize the carbocation intermediate, making the reaction faster. For elimination, we need a baseto attack a hydrogen "β" (1 carbon away) to the electrophilic carbon. (This is the opposite of S N 2 -protic solvents solvated the nucleophile making it less reactive. The nucleophile is not important in the S N 1 reaction.) Many compounds have different βhydrogens to choose from. Zaitsev's rulestates that the most stable, most substituted alkene product will be favored. ch11 Page 13 ch11 Page 14

8 11.8 The E2 reaction The anti-periplanar geometry The σbonds must be aligned anti-periplanar in order to make a πbond. Compare with the direction of attack of the nucleophile in an S N 2 reaction. Both nucleophile and base must come from the opposite direction of the leaving group. The E2 reaction requires a very specific arrangement of the atoms in order for the mechanism to be concerted. This has consequences for double-bond stereochemistry. ch11 Page 15 ch11 Page 16

9 11.9 The E2 reaction and cyclohexane conformation The anti-periplanar geometry only exists in a cyclohexane ring when a βh and the leaving group are trans and axial The E1 reaction If there's: no strong base 2 o or 3 o substrate protic solvent the leaving group will leave spontaneously to form a carbocation. Solvent can remove a proton to make the Zaitsef elimination product. Because of the same carbocation intermediate, E1 and S N 1 happen together. It will be a mixture of substitution and elimination products. If a t-butyl group prevents the H and LG from being axial, E2 elimination cannot occur. ch11 Page 17 ch11 Page 18

10 11.12 Summary of reactivity Synthesis practice Strong baseshave a R 3 C: -, R 2 N -, or RO - (no resonance) Strong nucleophiles include the above, PLUS these weak bases : R 3 N, RS -, Cl -, Br -, I -, Polar aprotic solventsdo not have any H-bonding (no OH, NH, or FH). Common solvents are acetone, DMF, THF, ethers, DMSO, CH 3 CN. These activate Nuc: - Polar protic solventshave an H-bond donor like ROH and H 2 O. These stabilize charged species(nuc: - or C+) All of these reactions require a good leaving group: for our purposes, Cl -, Br -, I -, OTs -, and H 2 O are common (they are RCl, RBr, RI, ROTs, and ROH 2+ in the substrate) S N 1/E1: 2 o or 3 o reactant, protic solvent (stabilizes C+ intermediate) and weakbase, neutral, or acidic conditions) - C+ resonance and rearrangement common. S N 2: 1 o or 2 o reactant (steric hindrance), strong nuc that's a weak base (prevents elim), and polar aprotic solvent (makes nuc more reactive) E2: 1 o, 2 o, or 3 o reactant, strong base, and ß hydrogen anti to LG (geometry required for E2) ch11 Page 19 ch11 Page 20