Lecture Outline Applications of Nucleophilic Substitution Chemistry

Name ______________________________________ Ch 10 contains an assortment of reactions that organic chemists frequently use to make molecules. The unifying theme is that they all involve SN2, E2, SN1, or E1 reactions. So let's review some of that chemistry... 1 (a) Draw the product of the SN2 reaction below. O Br + (b) Why will E2 not compete in this case? 2 If we wanted to do this reaction in the lab, we'd likely start with phenol, Ph–OH, rather than phenoxide, Ph–O–. What's the easiest way to completely deprotonate phenol (pKa = 10)? Some of the bases below are strong enough. Circle the weakest one (thus easiest to use) that is still strong enough to do the job. H2O CH3CO2Na NaHCO3 NH3 NaOH NaH NaNH2 3 The reaction below might be expected to make the same ether as the SN2 reaction in prob #1. But why does SN2 not work in this case? Br + O SN2 4 That same ether might also be made by SN1 chemistry — ionization of the allylic bromide in prob #1, followed by capture of the carbocation by Ph–OH. But this reaction would produce a mixture of SN1 products — the ether above plus a constitutionally isomeric ether. Why? If you understand, you will draw a key structure. 5 Now let's put this all together. Suppose you want to make the ether below in the best possible yield and purity. You can start with any neutral organic molecules containing 6 carbons or fewer. Write a sequence of reactions that could be used to make (synthesis) this ether. O Ph (we've just covered nearly everything in the first 4 sections of Ch 10) Lecture outline (we'll cover most of the material in Ch 10, excluding sections 10.6, 10.9, or 10.14) Applications of nucleophilic substitution chemistry Preparation of alcohols — Alkyl halides can be converted to alcohols in good yield by SN2 reactions — NaOH Br DMSO but E2 can be a problem when SN2 is sluggish, e.g., with 2° and β-branched 1°-halides Br Br This problem can be overcome by using a 2-step procedure (see text p 351) that uses a weaker base, acetate, as the nucleophile. Hydrolysis of the resulting ester yields the desired alcohol product. The mechanism of the base-induced ester hydrolysis ("saponification") is not presented clearly in the text until a much later chapter; we'll see how this works in class. HO– AcO– Br SN2 (+ no E2) H2O O OH O Let's add stereochemistry to the example above. Would you expect either direct SN2 with hydroxide or the two-step procedure with acetate to be successful with a 3° halide? How about a vinylic or aryl halide? Can we make alcohols by SN1 hydrolysis of organo-halides? In this case we'll have to put up with a bit of E1 — there's no way to prevent that, but fortunately it's a minor pathway. Which of the following alcohols could we make in decent yield and purity by SN1 chemistry? (assume all chiral alcohols below are racemic) OH OH OH OH OH Preparation of ethers — The SN2 route is called the Williamson Ether Synthesis. It has the usual scope and limitations that one would expect for SN2 chemistry. Here's an example... Cl + O Notice that the route above forms one of two C–O bonds of the ether. Could we use a similar route to make the other C–O bond instead? Note that we can't dodge the E2 issue in this case by using acetate as a surrogate nucleophile like we did to avoid E2 reactions induced by HO–. In general, the alkoxide nucleophile has to be made by deprotonating the corresponding alcohol. What common bases are strong enough to completely deprotonate an alcohol? Note that hydroxide is not strong enough to completely deprotonate the alcohol. Incomplete deprotonation is not a problem for many reactions, but if we're trying to make a nucleophile to use in an SN2 reaction, incomplete deprotonation is a disaster. Why? Another common method for converting alcohols to alkoxide ions is reaction with an alkali metal, usually sodium. R OH + Na• R O Na+ + H2 This is not an acid-base reaction - Na metal is not a base! Sodium acts as an electron donor; this is an oxidation-reduction reaction. Na is oxidized to Na+; hydrogen is reduced to H2 gas. Suppose we wanted to prepare the optically active ether below starting from an alcohol and an alkyl or alkenyl halide. How would we do that? Let's write a short synthesis of that ether. O Let's briefly revisit SN1 chem. We could certainly use SN1 chemistry to make an ether like tertbutyl methyl ether (tBu–O–CH3; how?). Can we use SN1 chemistry to make the more complex ether above? If we need to deprotonate a compound more acidic than a simple alcohol, a weaker base like NaOH or even NaHCO3 will do the job, so we're not going to go to the extra trouble of using Na metal or a super-strong base like NaH. How would we make the phenyl ether below via an SN2 route? Write a short synthesis starting from an alcohol and an organo-halide of your choice. O We can also use SN2 chemistry to make certain esters. Suggest a synthesis of the ester below starting from a carboxylic acid and an organo-halide. O O Could we instead put this ester together by making the other C–O bond? Yes — we'll learn how next semester — but not by SN2 chemistry! Remember, nucleophiles can't displace leaving groups directly (via SN2) from trigonal (sp2) carbons! All of these routes can also be used to make cyclic ethers and esters as well. Examples as time permits...