Lecture Outline SN2 Reaction Continued

Name ______________________________________ You've read sections 8.1 - 8.5 by now. The next few sections (6 - 8) discuss another nucleophilic substitution mechanism, the SN1 rxn, and the sections after that discuss both SN1 and SN2. We're going to skip SN1 for now and return to it a bit later. So for now, just pick out the SN2 bits and ignore the rest. Section 8.13 deals with intramolecular "SN2" reactions. 1 Draw the products of the two reactions in problem 8.17 on p 294. 2 Upon treatment with sodium bicarbonate, the bromo-carboxylic acid below undergoes a rapid acid-base reaction, followed by an intramolecular "SN2". Draw the product, showing its structure and stereochemistry clearly. (By structure, I mean draw out the "...CO2..." part so that it's absolutely clear what's bonded to what — no undefined clumps of atoms, please.) CO2H NaHCO3 Br 3 (bonus question) Why did I put SN2 in quotes? Lecture outline SN2 reaction continued... 4. Leaving group — weaker base = better leaving group (l.g.) Halide ions are very common leaving groups ("leaving atoms" would be ) I– Br– > > Cl– >> F– Strong bases, e.g., HO–, H2N–, H:–, are never displaced in SN2 rxns. Sulfonate ions are also good leaving groups. Two of the most common are methanesulfonate ("mesylate", MsO–) and p-toluenesulfonate ("tosylate", TsO–). These groups can be introduced by reaction of an alcohol OH with "mesyl chloride" or "tosyl chloride" by the method illustrated on pp 281 and 283 of the text. — but beware: those curvy arrows originating from the oxygen of 2-octanol on p 283 are NOT meant to suggest that these are SN2 displacements — that's why there's no arrow showing release of the chloride ion. Those reactions go by a different mechanism that we'll learn later. It involves addition of the nucleophilic oxygen to the carbonyl group followed by loss of Cl– in a separate step. Direct SN2 displacement of halide ion from an sp2 C has never been observed. Those arrows really shouldn't be there. . CH3 Ms–O O O S O S O O O Ts–O 5. Nucleophile — Here are some nucleophilicities measured by comparing rates of reactions of various nucleophiles with CH3–I in methanol solvent. The nucleophilicity parameters are defined as the log of the ratio of the rate constant, k, for the nucleophile listed reacting with CH3I vs k for methanol reacting with CH3I, which is very very slow. For example, n = 6.29 for methoxide (2nd entry) means that CH3O–attacks CH3I 106.29 times faster than CH3OH attacks CH3I. Nucleophile n = log(knuc/kMeOH) pKa of conj acid CH3OH CH3O– F– Cl– NH3 N3– Br– (CH3)2S I– (CH3)2Se CN– PhS– Ph3P CH3CO2– PhO– Et3N PhSe– HS– NO3– 0.00 6.29 2.7 4.37 5.5 5.78 5.79 5.54 7.42 6.32 6.70 9.92 7.00 4.3 5.75 6.66 10.7 8 1.5 – 1.7 15.7 3.45 –5.7 9.25 4.74 – 7.7 – 5.3 – 10.7 --9.3 6.52 2.73 4.75 9.89 10.70 --7.8 – 1.3 Data from RGPearson, HSobel, JSongstad JAmChemSoc, 1968, 90, 319-26. Now let's make some generalizations — a. Within a row of the periodic table, 2nd-row nucleophiles ... (fill in the conjugate acid pKas) RX H2O RCO2H ROH ROR conj acid pKa F RCO2 R3N: RO H3N: HO etc etc b. Down a column of the periodic table, Just like protonation, SN2 reactions of more basic nucleophiles tend to be more exothermic, and this is often reflected in a lower activation energy and a faster reaction — this is the primary effect going across a row of the periodic table. But that correlation is lost on going from small compact nucleophiles in the second row to larger nucleophiles (that are weaker bases) further down in the table. These SN2 reactions tend to be less exothermic, but because these species are more polarizable (meaning, in a sense, that the electrons can "slosh around" more easily), their reactions often have unusually low activation barriers. c. Steric bulk decreases nucleophilicity CH3—O is a better nucleophile than (CH3)3C—O (big surprise there, eh?) 6. Solvent — is not critical for the success of SN2 reactions, though these reactions generally go faster in aprotic than in protic solvents because protic solvents can hydrogen bond to and "tie up" the nucleophile. a. protic solvents — can hydrogen bond. Hydrogen bonding is a weak interaction between an electronegative atom of one molecule and an H bonded to an electronegative atom on another. Hydrogen bonding is common among molecules that have O–H or N–H bonds. For example, two alcohol molecules can hydrogen bond to each other. Hydrogen bonding among the !+ O H molecules of a liquid like methanol, CH3OH (bp 65°C), makes vaporization harder and thus gives the liquid a R higher boiling point than similar compounds that cannot hydrogen bond, e.g. CH3F (bp –78 °C) or CH3OCH3 (bp –25 °C). !– H O R The most common hydrogen bonding organic solvents are: H2O alcohols (ROH) carboxylic acids (RCO2H) amines (RNH2, R2NH) amides (RCONH2, RCONHR) These solvents can hydrogen bond strongly to small, basic nucleophiles like F–. This reduces a nucleophile's reactivity — it has to shed its shell of solvent molecules and give up the stabilization that it gains from solvation before it can do an SN2 reaction. RO–H H–OR F RO–H H–OR Big fluffy soft nucleophiles like I– don't have this problem. Because their charge is dispersed over a large surface area, protic solvents hydrogen bond to them only weakly or not at all. Thus, I– is a much better nucleophile than F– in protic solvents. b. aprotic solvents — cannot hydrogen bond. Some aprotic organic solvents are: O O acetone CH3 S CH3 O CH3 C N acetonitrile CH3 HC N dimethylsulfoxide (DMSO) N,N-dimethylformamide (DMF) CH3 These solvents are all polar and can therefore solvate ionic compounds (M+ Nuc–), but they do not interact strongly with anions (i.e. nucleophiles). Small, basic species are much more nucleophilic in aprotic than they are in protic solvents. (In fact, F– is a slightly better nucleophile than I– in aprotic solvents.) c. As discussed in the text (p 287), solvent polarity can affect the rate of the SN2 reaction, but whether the reaction goes faster or slower as solvent polarity increases depends on whether charge is created or dispersed upon going from the reactants to the transition state.