CHEM 203

Topics Discussed on Nov. 23

Desirability of a method for "alcohol activation" that would be stereochemically complementary to that involving reaction of an alcohol with P / S halides (notes of Nov 20):

PBr3 CH S Na 3 overall (inversion of H (inversion) H retention configuration) Br SMe (S)-2-bromobutane (R)-configured pdt. H OH (R)-2-butanol ? (S)-configured pdt. overall H inversion SMe

Sulfonyl chlorides: para-toluenesulfonyl ("tosyl") chloride, methanesulfonyl ("mesyl") chloride

O O O

R S Cl H3C S Cl S Cl O O O A generic sulfonyl methanesulfonyl chloride Toluene para-toluenesulfonyl chloride chloride: R = any ( "mesyl chloride" ) (= methyl benzene) ( "tosyl chloride" ) alkyl group

Pyridine: a weakly basic, nucleophilic analog of benzene in which an N atom replaces a CH unit:

pyridine N

Reaction of primary and secondary alcohols with sulfonyl chlorides in the presence of pyridine: formation of sulfonate esters (= alkyl sulfonates):

R1 O R1 O OH + Cl S R N O S R + R2 O R2 N O H Cl a generic primary or an "alkyl sulfonate" secondary alcohol ("tosylate", "mesylate," etc.)

note: tertiary alcohols are insufficiently nucleophilic to react with sulfonyl chlorides

Presumed mechanism for the formation of sulfonate esters from primary and secondary (but not tertiary) alcohols and sulfonyl chlorides:

• slow rate of reaction of an alcohol with sulfonyl chlorides in the presence of generic bases

Lecture of Nov. 23 p. 2

• pyridine as a nucleophilic catalyst that greatly accelerates the reaction of an alcohol with a sulfonyl chloride by:

(i) reacting with sulfonyl chloride first, leading to a complex …

Cl – O O O Cl S Cl S S N O O N O N notice the mechanistic similarity with the chemistry of SOCl 2

(ii) which reacts at a very fast rate with primary and secondary alcohols: – Cl – Cl O O N S N S O O R1 1 O R H OH R2 R2 notice the mechanistic similarity with the chemistry of SOCl 2

N Cl – R1 O Cl – H O O S + NH R1 2 O S R O 2 O R an alkyl tosylate protonated form of pyridine

note: the reasons why the pyridine-sulfonyl group complex reacts with alcohols at a much faster rate than the parent sulfonyl chloride will be discussed in more advanced courses.

Sulfonic acids such as para-toluenesulfonic acid or methanesulfonic acids as strongly Bronsted acidic agents (sulfuric acid-like!!)

O O O

R S OH H3C S OH S OH O O O A generic sulfonic methanesulfonic acid Toluene para-toluenesulfonic acid: R = alkyl group (= methyl benzene) acid

Anions of sulfonic acids, i.e., sulfonate ions, as excellent leaving groups in SN2 and E2 reactions, due to the fact that they are the conjugate bases of strong Bronsted acids (the parent sulfonic acids have pKa ≤ 0):

O O para-toluenesulfonate S O H C S O methanesulfonate ion 3 ion O O

Lecture of Nov. 23 p. 3

Principle: alkyl sulfonates undergo SN2 and E2 reaction in a manner essentially identical to that of alkyl halides

Substitution reactions of sulfonate esters; e.g.:

O Li NaN3 S O H N3 S 2 Cu(I)Br H N O H (S)-2-azidobutane (R)-2-butyl tosylate

Stereochemical complementarity of sulfonate ester vs. PBr3 technology:

PBr 3 CH3S Na

(inversion of H (inversion) H configuration) Br SMe (S)-2-bromobutane (R)-configured pdt. H enantiomers! OH TsCl pyridine (R)-2-butanol CH3S Na H H (retention of OTs (inversion) SMe configuration) (S)-configured pdt. (R)-2-butyl tosylate

one may thus access either enantiomer of a product of SN2 reaction of a suitably activated alcohol by the judicious choice of the activation method: sulfonate technology produces overall inversion of configuration; PBr3 technology, overall retention (via a double inversion)

E2 reactions of sulfonate esters; e.g.:

O O K S O O E2

Possible mode of activation of the α-H of a primary or secondary alcohol:

H H 1 α connect a potential α induce an R R1 C OH R1 C O C O leaving group L to elimination 2 R2 the oxygen atom R2 L reaction R a generic primary or a carbonyl compound secondary alcohol

Principle: activation of the α-H of a primary or secondary alcohol as seen above results in the conversion of the starting alcohol into a carbonyl compound

Lecture of Nov. 23 p. 4

The conversion of an alcohol into a carbonyl compound as an oxidation reaction

oxid. st. = –1 if R2 = H oxid. st. = +1 if R2 = H oxid. st. = 0 if R2 = alkyl oxid. st. = +2 if R2 = alkyl H R1 R1 C OH C R2 O R2 the OH-bearing C atom goes from the oxidation state of –1 or 0 to that of +1 or +2: it undergoes a two-electron oxidation; so "something else" must undergo a two-electron reduction...

Principle: the leaving group L in the above reaction must undergo a two-electron reduction

Principle: the leaving group L in the above reaction is often a metal in a high oxidation state

Chromium (VI) as an especially valuable metal for the above reactions

Oxidation of alcohols to carbonyl compounds with Cr(VI) – based reagents

Chromiun trioxide, CrO3 (inexpensive industrial chemical), as a convenient source of Cr(VI)